1,3,4-thiadiazoles and 1,3,4-oxadiazoles as IIb/IIIa antagonists

ABSTRACT

##STR1## This invention relates to improved isoxazoline compounds including, but not limited to 1,3,4-thiadiazoles and 1,3,4-oxadiazoles of the formula which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

FIELD OF THE INVENTION

The present invention relates generally to 1,3,4-thiadiazoles and 1,3,4-Oxadiazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.

Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.

Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.

Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A₂ synthetase inhibitors or receptor antagonists, which act against thromboxane A₂ ; and hirudin, which acts against thrombin.

Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.

GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.

Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.

European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR2##

European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR3##

European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR4##

PCT Patent Application 9307867 relates to compounds having the general formula: ##STR5##

European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR6##

Copending commonly assigned U.S. patent application Ser. No. 08/337,920 (filed Nov. 10, 1994, Wityak et al.; published as WO95/13155, Jun. 1, 1995) discloses compounds having the general formula: ##STR7## which are useful as IIb/IIIA antagonists.

Copending commonly assigned U.S. patent application Ser. No. 08/455,768) (filed May 31, 1995, Voss et al.) discloses compounds having the general formula: ##STR8## which are useful as α_(v) β₃ antagonists.

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

SUMMARY OF THE INVENTION

One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.

Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of the Formula I: ##STR9## and their enantiomeric, diastereomeric, pharmaceutically acceptable salt or prodrug forms thereof wherein:

R¹ is selected from R² HN--, R² HN(R² N═)C--, R² HN(CH₂)_(q) Z--, R² HN(R² N═)C(CH₂)_(q) Z--, R² HN(R² N═)CN(R²)--, R² HNC(O)--, R² (R⁵ O)N(R² N═)C--, or R² HN(R⁵ ON═)C--;

alternatively, R¹ is H when Ar is -(piperidinyl)-;

q is 1-3;

Z is selected from a bond (i.e. is absent), O, S, or S(═O), S(═O)₂ ;

R² is selected from H, aryl(C₁ -C₁₀ alkoxy) carbonyl, or C₁ -C₁₀ alkoxycarbonyl, C₁ -C₄ alkyl, C₃ -C₆ alkenyl;

R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-1 R^(4b) ;

R^(4b) is selected from C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₇ cycloalkyl, C₇ -C₁₄ bicycloalkyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³ ; halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;

Ar is selected from:

-(piperidinyl)- substituted with 0-2 R^(6a),

-(phenyl)- substituted with 0-2 R^(6a), or

-(pyridyl)- substituted with 0-2 R^(6a) ;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

A is selected from O or S;

W is selected from --(CH₂)_(n) -- or --S(CH₂)_(n-1) --;

X is selected from --C(CH₂ --Ph)H--, --CH₂ --, --CH₂ C(NHR¹²)H-- or --C(CH₂ NHR¹²)H--;

Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R²)HN--(C₁ -C₁₀ alkoxy)--;

m is 0-2;

n is 1-4; and

R¹² and R¹³ are each independently selected from H; C₁ -C₁₀ alkyl; C₁ -C₁₀ alkoxycarbonyl; C₁ -C₁₀ alkylcarbonyl; C₁ -C₁₀ alkylsulfonyl; aryl, aryl(C₁ -C₁₀ alkyl)sulfonyl, and arylsulfonyl wherein said aryls and heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and heteroaryl(C₁ -C₄ alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl wherein said heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;

provided that m and n are chosen such that the number of atoms connecting R¹ and Y is in the range of 10-18.

Preferred compounds of the present invention are compounds of the formula I wherein:

R¹ is selected from R² NHC(═NR²)-- or R² NHC(═NR²)NH--;

R² is selected from H, C₁ -C₁₀ alkoxycarbonyl, or C₁ -C₄ alkyl;

R⁵ is selected from H or C₁ -C₄ alkyl

Ar is selected from -(phenyl)- substituted with 0-2 R^(6a), or -(piperidinyl)- substituted with 0-2 R^(6a) ;

R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ;

A is selected from O or S;

W is selected from --(CH₂)_(n) -- or --S(CH₂)_(n-1) --;

X is selected from --CH₂ C(NHR¹²)H-- or --C(CH₂ NHR¹²)H--;

Y is selected from:

hydroxy;

C₁ to C₁₀ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

m is 1 or 2;

n is 1 or 2;

R² is selected from H; C₁ -C₆ alkyl; C₁ -C₄ alkoxycarbonyl; C₁ -C₆ alkylcarbonyl; C₁ -C₆ alkylsulfonyl; aryl, aryl(C₁ -C₄ alkyl)sulfonyl, and arylsulfonyl wherein said aryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and heteroaryl(C₁ -C₄ alkyl)sulfonyl, heteroarylsulfonyl, heteroarylcarbonyl or heteroarylmethylcarbonyl wherein said heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and

R¹³ is H.

The most preferred compounds of the present invention are:

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol -5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt

Methyl N³ -[2-{2-(4-N,N'-di(trifluoroethyl)amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt

Methyl N³ -[2-{2-(4-N-hydroxyamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[2-{2-(4-amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

N³ -[2-{2-(4-Amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

N³ -[2-{2-(4-Amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt

Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N² -(n -butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine

Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine TFA salt

Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine TFA salt

Ethyl N-[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine HCl salt

Methyl N² -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N3-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N² -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

Methyl N² -[2-{2-(4-amidinophenyl)-1,3,4-thiodiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

The compounds of Formula I of the present invention are useful for the treatment (including prevention) of thromboembolic disorders. The term "thromboembolic disorders" as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.

The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.

Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.

The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.

Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.

The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.

The compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.

By "therapeutically effective amount" it is meant an amount of a compound of Formula I that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin™) and heparin.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane™. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin and other inhibitors of thrombin synthesis such as Factor XA. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.

The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase™. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The compounds or combination products of the present invention may also be useful for the treatment, including prevention, of metastatic cancer.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.

The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

When any variable (for example but not limited to, R¹, R², R^(4b), R^(6a), R¹², and R¹³, n, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence.

When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.

When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperidinyl, piperidinyl, or morpholinyl, unless specified otherwise, said piperidinyl, piperidinyl, morpholinyl group may be bonded to the rest of the compound of Formula I via any atom in such piperidinyl, piperidinyl, morpholinyl group.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "C₁ -C₁₀ " denotes alkyl having 1 to 10 carbon atoms); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

The terms "alkylene", "alkenylene", "phenylene", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such "alkylene", "alkenylene", "phenylene", and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", "-(alkenyl)-" and "-(phenyl)-", and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl optionally substituted with 0-3 groups independently selected from methyl, methoxy, amino, hydroxy, halogen, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, CF₃, S(O)_(m) CH₃, --N(CH₃)₂, C₁ -C₄ haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; the term "arylalkyl" represents an aryl group attached through an alkyl bridge.

As used herein, the term "heteroaryl" refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.

As used herein, the term "chiral amine" refers to any amine containing compound that also contains a chiral center. Such compounds include, by way of example and without limitation, either enantiomer of cinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. Examples the prodrug forms of the compounds of the present invention include the following esters:

methyl; ethyl; isopropyl; methylcarbonyloxymethyl-; ethylcarbonyloxymethyl-; t-butylcarbonyloxymethyl-; cyclohexylcarbonyloxymethyl-; 1-(methylcarbonyloxy)ethyl-; 1-(ethylcarbonyloxy)ethyl-; 1-(t-butylcarbonyloxy)ethyl-; 1-(cyclohexylcarbonyloxy)ethyl-; i-propyloxycarbonyloxymethyl-; cyclohexylcarbonyloxymethyl-; t-butyloxycarbonyloxymethyl-; 1-(i-propyloxycarbonyloxy)ethyl-; 1-(cyclohexyloxycarbonyloxy)ethyl-; 1-(t-butyloxycarbonyloxy)ethyl-; dimethylaminoethyl-; diethylaminoethyl-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-; 1-(2-(2-methoxypropyl)-carbonyloxy)ethyl-.

The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.

As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The following abbreviations are used herein:

    ______________________________________                                         Boc          tert-butyloxycarbonyl                                             Boc.sub.2 O  di-tert-butyl dicarbonate                                         Cbz          benzyloxycarbonyl                                                 DEC          1-(3-dimethylaminopropyl)-3-                                                   ethylcarbodiimide hydrochloride                                   DIEA         diisopropylethylamine                                             DMAP         4-dimethylaminopyridine                                           DMF          N,N-dimethylformamide                                             EtOAc        ethyl acetate                                                     EtOH         ethyl alcohol                                                     pyr          pyridine                                                          TBTU         2-(1H-Benzotriazol-1-yl)-1,1,3,3-                                              tetramethyluronium tetrafluoroborate                              TFA          trifluoroacetic acid                                              THF          tetrahydrofuran                                                   ______________________________________                                    

The central synthetic portion of the current invention is the construction of the four heterocycle cores, 1,3,4-thiadiazole, 1,3,4-oxadiazole, 1,3,4-oxadiazol-2-yl-sulfide and 1,3,4-thiadiazol-2-yl-sulfide, which are presented in the compounds claimed in this invention. Generally, a compound useful as fibrinogen receptor antaganist is made from an intermediate acid with one of the four heterocycle core structures mentioned above.

Scheme I represents a general synthetic sequence to the thiadiazole(1-5) which is a key intermediate acid for the syntheses of the compounds of this invention. An appropriately substituted ester(1-1) is treated with hydrazine monohydrate to afford the hydrazide(1-2) which is then converted to the N,N'-diacylhydrazine(1-3) on reaction with an acid chloride in aqueous THF using NaHCO3 as base. The N,N'-diacylhydrazine thus obtained can be readily cyclized to give the 1,3,4-thiadizole(1-4) using Lawessen reagent (M. P. Cava, et al, Tetrahedron 1985, 41, 5061). This cyclization could also be effected by using reagents such as P2S5 as reported by Stolle, et al (J Prakt. Chem 1904, 69, 145). The hydrolysis of the ester(1-4) using LiOH in aqueous THF affords the 1,3,4-thiadiazole(1-5). ##STR10##

Cyclodehydration of the N,N'-diacylhydrazine(1-3) using POCl3 according to the method of Klingsberg (J. Am. Chem. Soc. 1958, 80, 5788) followed by a LiOH hydrolysis (Scheme II) readily gives the 1,3,4-oxadiazole(2-3), which is another key intermediate acid for the syntheses of the compounds claimed in this invention. Other dehydrating agents including chlorosulfonic acid (Ger. Pat. 825111[C.A.1955,49,630]), sulfuryl chloride, (Ger. Pat. 825111[C.A.1955,49,630]), phosphorus pentoxide (Stolle, et al, J. Prakt. Chem. 1904, 69, 382), p-toluenesulfonic acid (Ger. Pat. 825111[C.A.1955,49,630]) may be used to bring about this cyclodehydration. ##STR11##

The 1,3,4-oxadiazol-2-yl-sulfide(3-2) may be obtained directly from the hydrazide(3-1) adopting the method of Confalone, et al (J. Am. Chem. Soc. 1983, 105, 902)(Scheme III). The hydrazide(3-1) is first treated with ethanolic potassium hydroxide, then with carbon disulfide and finally with an appropriately substituted halide (or other electrophiles) upon heating to afford the key intermediate acid 1,3,4-oxadiazol-2-yl-sulfide(3-2). ##STR12##

Scheme IV depicts a general synthetic sequence to the 1,3,4-thiadiazol-2-yl-sulfide(4-5) which is also an key intermediate acid for the preparation of the compounds of this instant invention. An appropriately substituted acid chloride(4-1) is treated with benzyldithiocarhydrazide in pyridine to yield the acyldithiocarbazate(4-2), which cyclizes under conditions of refluxing benzene in the presence of p-toluenesulfonic acid according to the method of Fujii et al (J. Pharm. Soc. Japan 1954, 74, 1056) and Young et al (J. Am. Chem. Soc. 1955, 77, 400). The concentrated sulfuric acid can also be used to bring about this cyclization. Oxidation of the sulfide(4-3) using common oxidants such as potassium permanganate give the corresponding sulfone(4-4), which is converted to the desired 1,3,4-thiadiazol-2-yl-sulfide(4-5) on treatment with an appropriately substituted thiol in the presence of a suitable base such as triethylamine. ##STR13##

Compounds of the instant invention can be prepared from the above four acids 1-5, 2-3, 3-2, 4-5 via a coupling with an appropriately substituted α- or β- amino ester using standard coupling reagents, such as DCC/HOBt, followed by suitable substitute modifications, among which are the nitrile-to-amidine and amine-to-guanidine transformations. Examples are given below to show these synthetic protocols.

In Scheme V, the nitrile acid(5-1), which is prepared according to the synthetic sequence presented in Scheme I, is coupled with the amino ester(5-2) using TBTU as coupling reagent to afford the nitrile amide(5-3). The nitrile amide is then converted to the amidine via the imidate under standard conditions followed by ester hydrolysis(LiOH in aq. THF or 4N HCl). Compounds claimed in this invention can be readily prepared by combining the synthetic protocols depicted in Scheme I-V. ##STR14##

Compounds of Formula I wherein R1 is R2HN(R2N═)CN(R2)-- are prepared as illustrated in Scheme VI. The nitrile acid(6-1) obtained according to the synthetic route depicted in Scheme II is coupled with an appropriately substituted amino ester(6-2) using the conditions described in Scheme V to provide the nitrile amide(6-3), which is converted to the amine amide(6-4) by catalytic hydrogenation. The transformation of the amine(6-4) to the guanidine(6-5) is brought about by using the method described by Kim, et al (Tetrahedron Lett. 1993, 48, 7677). ##STR15##

The conversion of a nitro compound to an amine as shown in Scheme VI provides a synthesis to the compounds of formula I wherein R1 is R2HN-- or R2HN(CH2)qZ--. These compounds may also be prepared by deprotection of the protected amines as illustrated in Scheme VII. ##STR16##

Compounds of formula I wherein R1 is R2HNC(O)-- may be prepared by reaction of the corresponding nitrile with an appropriate alcohol under acidic conditions (J. Med. Chem. 1991, 34, 851) or with hydrogen peroxide under basic conditions (J. Am. Chem. Soc. 1958. 80, 2257).

Compounds of Formula I Wherein R1 is R2(R5O)N(R2N═)C-- or R2HN(R5N═)C-- may be prepared by reaction of the corresponding nitrile with an appropriately substituted hydroxyamine.

A further example is given in Scheme VIII to show an alternative synthetic sequence to the compounds of this invention. The hydrazide(8-1), after treated with methanolic potassium hydroxide and carbon disulfide, is captured directly with an amide halide(8-2) to give the nitrile amide(8-3), which is converted to the amidine(8-4) under the normal conditions as mentioned above. ##STR17##

The appropriately substituted α- or β- amino acids may be purchased commercially or synthesized conventionally. The synthesis of N² -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981).

The compounds of this invention and their preparation can be further understood by the following procedures and examples, which exemplify but do not constitute a limit of their invention.

EXAMPLE 1

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. 4-Cyanobenzoylhydrazine

A mixture of methyl 4-cyanobenzoate(10.8 g, 67 mmol) and hydrazine monohydrate(18.6 g, 371 mmol) in absolute ethanol(70 ml) was heated to reflux for 3 hrs and then was allowed to cool down to rt. The solid portion was collected by filtration and washed with cold ethanol(20 ml) and then dried to give the product(8.7 g, 81% yield). M.P.: 201° C. ¹ H NMR(300 MHz, CDCl₃) δ4.14(s, 2H), 7.40(s, 1H), 7.76(d, J=8, 2H), 7.88(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 162. Found: 162.

Part B. N-(4-cyanobenzyl)-N'-(2-methoxycarbonylacetyl)hydrazine

To a suspension of 4-cyanobenzoylhydrazine(500 mg, 3.1 mmol) in aqueous THF(10 ml, 1:1 v/v) containing sodium bicarbonate(290 mg, 3.4 mmol), cooled with ice-water, was added methyl malonyl chloride(470 mg, 3.4 mmol) dropwise. After addition, the ice-water bath was removed and the mixture was stirred at rt for 2 hrs. The THF was evaporated under reduced pressure and the product as a solid powder was then collected by filtration and dried. (650 mg, 80% yield). ¹ H NMR(300 MHz, CDCl₃) δ3.45(s, 2H), 3.80(s, 3H), 7.78(d, J=8, 2H), 7.95(d, J=8, 2H), 9.5(d, J=6, 1H), 10.2(d, J=6, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 262. Found: 262.

Part C. Methyl 2-[2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl]acetate

A mixture of N-(4-cyanobenzoyl)-N'-(2-methoxycarbonylacetyl)hydrazine(1 g, 3.8 mmol) and Lawesson's reagent(780 mg, 1.9 mmol) in anhydrous THF(15 ml) was gently refluxed for 1 hr. The solution was then evaporated to dryness and the residue washed with ethyl acetate. Crystallization of the solid thus obtained afforded the product(680 mg, 73% yield). ¹ H NMR(300 MHz, CDCl₃) δ3.83(s, 3H), 4.26(s, 2H), 7.70(d, J=8, 2H), 8.10(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 260. Found: 260.

Part D. 2-[2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl]acetic acid

Methyl 2-[2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl]acetate(1 g, 3.7 mmol) was suspended in a mixture solvent of methanol, THF and water(30 ml, 1:1:1 v/v/v) containing lithium hydroxide monohydrate(170 mg, 4.0 mmol). The resulting mixture was stirred at rt for 2 hrs and then evaporated to dryness. The residue was washed with water(10 ml) and then dried(810 mg, 85% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ4.38(s, 2H), 8.0(d, J=8, 2H), 8.20(d, J=8, 2H); MS(NH₄ -DCI) Calc. for (M+1)⁺ : 256. Found: 256.

Part E. Methyl N² -Cbz-L-2,3-diaminopropionate HCl salt.

N² -Cbz-L-2,3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in 20 mL methanol and 20 mL 4N HCl in dioxane and the solution was stirred for 4 hours and then concentrated to give a solid. The solid was washed with ether several times to give 2.50 g (87%) product. NMR (DMSO-d₆): δ8.38(b, 3H); 7.96(d, 1H); 7.38(m, 5H); 5.05(s, 2H); 4.44(m, 1H); 3.66(s, 3H); 3.14(m, 2H).

Part F: Methyl N² -Cbz-N³ -Boc-L-2,3-diaminopropionate.

To a solution of methyl N² -Cbz-(S)-2,3-diaminopropionate HCl salt (16.3 mmol, 4.7 g) and di-tert-butyl dicarbonate (16.3 mmol, 3.56 g) in 30 mL chloroform cooled in an ice bath was added triethylamine (34 mmol, 4.7 mL) and the solution was stirred in the ice bath for 1 hour and at room temperature for 3 hours and concentrated. The residue was taken up in ethyl acetate and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR (DMSO-d₆): δ7.60(d, 1H); 7.35(m, 5H); 6.88(t, 1H); 5.02(s, 2H); 4.14(m, 1H); 3.60(s, 3H); 3.28(m, 2H); 1.37(s, 9H).

Part G: Methyl N³ -Boc-(S)-2,3-diaminopropionate Formic acid salt.

A mixture of methyl N² -Cbz-N³ -Boc-(S)-2,3-diaminopropionate. (14 mmo, 5.0 g), formic acid (42 mmol, 1.6 mL) and 10% Pd/C (500 mg) in 40 mL methanol was stirred at room temperature for 1 hour and filtered through a celite. The filtrate was concentrated and the residue was triturated with ether-petroleum ether to give 3.7 g (100%) solid product. NMR (DMSO-d₆): δ8.20(s, 1H); 6.90(t, 1H); 5.36(b, 3H); 3.61 9s, 3H); 3.51(t, 1H); 3.18(t, 2H); 1.38(s, 9H).

Part H: Methyl N² -n-butyloxycarbonyl-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt (14 mmol, 3.7 g) and NaHCO₃ (40 mmol, 3.4 g) in 10 mL water and 10 mL THF cooled in an ice bath was added slowly butyl chloroformate (16 mmol, 2 mL) over 15 min. After stirring for 1 hour, ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated to give 4.4 g (100%) oily product. NMR (DMSO-d₆): δ7.37(d, 1H); 6.84(t, 1H); 4.10(m, 1H); 3.96(t, 2H); 3.60(s, 3H); 3.26(m, 2H); 1.52(m, 2H); 1.38(s, 9H); 1.36(m, 2H); 0.88(t, 3H).

Part I: Methyl N² -n-butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt.

Methyl N² -n-butyloxycarbonyl-N³ -Boc-(S)-2,3-diaminopropionate (13.9 mmol, 4.4 g) was dissolved in 25 mL methylene chloride and 35 mL TFA and after 1 hour, the solution was concentrated to give an oily product. Yield 4.8 g (100%). NMR (DMSO-d₆): δ8.02(b, 3H); 7.68 (d, 2H); 4.38(m, 1H); 3.99(t, 2H); 3.68(s, 3H); 3.22(m, 1H); 3.06(m, 1H); 1.55(m, 2H); 1.34(m, 2H); 0.89(t, 3H).

Part J: Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

To a mixture of 2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetic acid(650 mg, 2.65 mmol), methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt(970 mg, 2.9 mmol) and triethylamine(1.07 g, 10.6 mmol) in DMF(15 ml), cooled with ice-water, was added TBTU(940 mg, 2.9 mmol). After stirring for 3 hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHCO₃ and brine successively, then dried. Concentration followed by chromatography with ethyl acetate as the eluent gave the product as an amorphous solid(860 mg, 73% yield). ¹ H NMR(300 MHz, CDCl₃) δ0.91(t, J=6, 3H), 1.30(m, 2H), 1.60(m, 2H), 3.70(m, 2H), 3.81(s, 3H), 4.04(t, J=6, 2H), 4.18(s, 2H), 4.50(m, 1H), 5.70(s, 1H), 7.06(s, 1H), 7.80(d,J=8, 2H), 8.10(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 446. Found: 446.

Part K. Methyl N³ -[2-{2-(4-formamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Dry HCl gas was bubled through a solution of Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(butyloxycarbonyl)-2,3-(S)-diaminopropionate(380 mg 0.85 mmol) in dry CHCl₃ containing anhydrous methanol(41 mg, 1.3 mmol), cooled with salt ice-water bath, at 0° C. for 5 hrs. The resulting solution was then kept at 0° C. for 6 hrs and at 15° C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol(7 ml) followed by addition of ammonium bicarbonate(240 mg, 2.1 mmol). After stirring at rt for 5 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give a white amorphous solid(220 mg, 56% yield). Further purification by reversed phase HPLC using water and 0.1% TFA in acetonitrile as eluent gave the TFA salt. ¹ H NMR(300 MHz, DMSO-d₆) δ0.88(t, J=6, 3H), 1.30(m, 2H), 1.50(m, 2H), 3.40(m, 2H), 3.60(s, 3H), 3.94(t, J=6, 2H), 4.01(m, 1H), 4.20(s, 2H), 7.56(s, broad, 1H), 7.98(d,J=8, 2H), 8.2(d, J=8, 2H), 8.70(m, 1H), 9.42(s, 1H), 9.58(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 463. Found: 463.

EXAMPLE 2

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt

A solution of methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate(110 mg, 0.24 mmol) in 4N HCl(6 ml) was stirred at rt for 48 hrs. Evaporation under reduced pressure and purification by reversed phase HPLC gave the acid salt(98 mg, 85% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ0.88(t, J=6, 3H), 1.30(m, 2H), 1.50(m, 2H), 3.40(m, 2H), 3.94(t, J=6, 2H), .01(m, 1H), 4.20(s, 2H), 7.56(s, broad, 1H), 7.98(d,J=8, 2H), 8.2(d, J=8, 2H), 8.70(m, 1H), 9.42(s, 1H), 9.58(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 449. Found: 449.

EXAMPLE 25

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N² -3-methylphenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N³ -BOC-(S)-2,3-diaminopropionate HCO₂ H salt (3.8 g, 14.7 mmol) and diisoproppylethylamine (3.3 g, 32.3 mmol) in CH₂ Cl₂ (60 ml), cooled with ice-water, was added 3-methylsulfonyl chloride (3.1 g, 16.2 mmol). After stirring at rt for 24 hrs, the resulting reaction mixture was diluted with ethyl acetate(150 ml), washed with dilute citric acid, saturated NaHCO₃ and brine, and then dried. Concentration afforded the product as a foam(5.1 g, 95% yield). ¹ H NMR(300 MHz, CDCl₃) δ1.58(s, 9H), 2.30(s, 3H), 2.72(m, 1H), 2.98(m, 1H), 4.10(m, 1H), 5.80(s, 1H), 7.40(d, J=5, 2H), 7.50(m, 1H), 7.56(s, 1H), 8.40(d, J=6, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 373. Found: 373.

Part B. Methyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt

Methyl N² -3-methylphenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate(4.5 g, 12.1 mmol) was dissolved in dioxane(8 ml) and then 4N HCl in dioxane(8 ml) was added. The resulting solution was stirred at rt for 5 hrs and then evaporated to give a foam(3.7 g, 100% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ2.40(s, 3H), 2.86(m, 1H), 3.10(m, 1H), 3.40(s, 3H), 4.28(m, 1H), 7.48(d,J=5 2H), 7.60(m, 1H), 7.62(s, 1H) 8.39(s, broad, 2H), 8.62(d, J=6, 1H); MS(ESI) Calc. for (M+1)⁺ : 273. Found: 273(free base).

Part C. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(s)-diaminopropionate

To a mixture of 2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetic acid(1.13 g, 4.61 mmol), methyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt(1.42 g, 4.61 mmol) and triethylamine(1.87 g, 18.4 mmol) in DMF(15 ml), cooled with ice-water, was added TBTU(1.48 mg, 4.61 mmol). After stirring for 3 hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHCO₃ and brine successively, then dried. Concentration followed by chromatography with ethyl acetate as the eluent gave the product as an amorphous solid(1.5 g, 65% yield). ¹ H NMR(300 MHz, CDCl₃) δ2.40(s, 3H), 3.58(m, 1H), 3.60(s, 3H), 3.78(m, 1H), 4.10(m, 1H), 4.20(s, 2H), 5.80(s, broad, 1H), 7.10(s, broad, 1H), 7.40(d, J=5, 2H), 7.60(m, 1H), 7.64(s, 1H), 7.80(d, J=8, 2H), 8.10(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 500. Found: 500.

Part D. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Dry HCl gas was bubled through a solution of methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(510 mg, 1.02 mmol) in dry CHCl₃ containing anhydrous methanol(40 mg, 1.2 mmol), cooled with salt an ice-water bath, at 0° C. for 5 hrs. The resulting solution was then kept at 0° C. for 6 hrs and at 15° C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol(8 ml) followed by addition of ammonium bicarbonate(200 mg, 2.0 mmol). After stirring at rt for 4 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give a white amorphous solid(480 mg, 91% yield). Further purification by reversed phase HPLC using water and 0.1% TFA in acetonitrile as eluent gave the TFA salt. ¹ H NMR(300 MHz, DMSO-d₆) δ2.34(s, 3H), 3.23(m, 1H), 3.38(s, 3H), 3.40(m, 1H), 3.90-4.10(m, 3H), 7.40(m, 2H), 7.58(m, 2H), 8.00(d, J=8, 2H), 8.20(d, J=8, 2H), 8.46(d, J=8, 1H), 8.82(t, J=6, 1H), 9.56(s, 1H), 9.62(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 517. Found: 517.

EXAMPLE 26

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

A solution of methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(100 mg, 0.19 mmol) in 6N HCl(4 ml) was stirred at rt for 20 hrs. Evaporation under reduced pressure and purification by reversed phase HPLC gave the acid salt(90 mg, 87% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ2.30(s, 3H), 3.10(m, 1H), 3.34(m, 1H), 3.94-4.10(m, 3H), 7.38(m, 2H), 7.56(m, 2H), 8.00(d, J=8, 2H), 8.18(d, J=8, 2H), 8.40(d, J=8, 1H), 8.80(t, J=6, 1H), 9.50(s, 1H), 9.62(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 503. Found: 503(free base).

EXAMPLE 44

Methyl N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Dry HCl gas was bubled through a solution of methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(400 mg, 0.80 mmol) in dry CHCl₃ containing anhydrous methanol(79 mg, 2.4 mmol), cooled with a salt ice-water bath, at 0° C. for 5 hrs. The resulting solution was then kept at 0° C. for 6 hrs and at 15° C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol(7 ml) followed by addition of 2N methylamine in methanol(0.8 ml, 1.6 mmol). After stirring at rt for 2 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give a yellow amorphous solid(325 mg, 77% yield). Further purification by reversed phase HPLC using water and 0.1% TFA in acetonitrile as eluent gave the TFA salt. ¹ H NMR(300 MHz, DMSO-d₆) δ1.90(s, 3H), 2.36(s, 3H), 3.20(m, 1H), 3.38(s, 3H), 3.42(m, 1H), 3.90-4.10(m, 3H), 7.40(m, 2H), 7.58(m, 2H), 7.90(d, J=8, 2H), 8.20(d, J=8, 2H), 8.40(d, J=8, 1H), 8.70(t, J=4, 1H); MS(ESI) Calc. for (M+1)⁺ : 531. Found: 531.

EXAMPLE 63

N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

A solution of methyl N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(100 mg, 0.19 mmol) in 4N HCl(3 ml) was stirred at rt for 50 hrs. Evaporation under reduced pressure and purification by reversed phase HPLC gave the acid salt(71 mg, 68% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ2.00(s, 3H), 2.40(s, 3H), 3.26(m, 1H), 3.40(m, 1H), 3.90-4.10(m, 3H), 7.38(m, 2H), 7.60(m, 2H), 8.00(d, J=8, 2H), 8.30(d, J=8, 2H), 8.40(d, J=6, 1H), 8.80(t, J=4, 1H); MS(ESI) Calc. for (M+1)⁺ : 517. Found: 517(free base).

EXAMPLE 64

Methyl N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

This compound was prepared analogously to Example 44.

¹ H NMR(300 MHz, DMSO-d₆) δ0.96(t, J=6, 3H), 1.40(m, 4H), 1.60(t, J=6, 2H), 2.34(s, 3H), 3.36(m, 1H), 3.38(s, 3H), 3.40(m, 1H), 3.98(m, 1H), 4.02(d, J=16, 1H), 4.10(d, J=16, 1H), 7.40(m, 2H), 7.56(m, 2H), 7.90(d, J=8, 2H), 8.10(d, J=16, 2H), 8.60(d, J=6, 1H), 8.76(t, J=5, 1H); MS(ESI) Calc. for (M+1)⁺ : 573. Found: 573.

EXAMPLE 65

N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

A solution of methyl N³ -[2-{2-(4-N-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(300 mg, 0.52 mmol) in 4N HCl(9 ml) was stirred at rt for 45 hrs. Evaporation under reduced pressure and purification by reversed phase HPLC gave the acid salt(246 mg, 79% yield). MS(ESI) Calc. for (M+1)⁺ : 559. Found: 559.

EXAMPLE 88

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N² -2-methylphenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate.

To a mixture of methyl N³ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt (2.58 g, 10 mmol) and diisoproppylethylamine(2.2 g, 22 mmol) in CH₂ Cl₂ (50 ml), cooled with ice-water, was added 2-methylsulfonyl chloride(2.1 g, 11 mmol). After stirring at rt for 24 hrs, the resulting reaction mixture was diluted with ethyl acetate(120 ml), washed with dilute citric acid, saturated NaHCO₃ and brine, and then dried. Concentration afforded the product as a foam(3.3 g, 90% yield). ¹ H NMR(300 MHz, CDCl₃) δ1.42(s, 9H), 2.68(s, 3H), 3.48(m, 2H), 3.58(s, 3H), 3.92(m, 1H), 4.94(s, broad, 1H), 5.79(d, J=5, 2H), 7.30(m, 2H), 7.45(t J=7, 1H), 7.94(d, J=7, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 373. Found: 373.

Part B. Methyl N³ -2-methylsulfonyl-(S)-2,3-diaminopropionate HCl salt

Methyl N² -2-methylphenylsulfonyl-N³ -Boc-(S)-2,3-diaminopropionate(3.5 g, 9.4 mmol) was dissolved in dioxane(8 ml) and then 4N HCl in dioxane(8 ml) was added. The resulting solution was stirred at rt for 5 hrs and then evaporated to give a foam(2.9 g, 100% yield). MS(ESI) Calc. for (M+1)⁺ : 273. Found: 273(free base).

Part C. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(s)-diaminopropionate

To a mixture of 2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetic acid(1.13 g, 4.61 mmol), methyl N² -2-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt (1.42 g, 4.6 mmol) and triethylamine(1.87 g, 18.4 mmol) in DMF(15 ml), cooled with ice-water, was added TBTU(1.48 mg, 4.61 mmol). After stirring for 3 hrs, the reaction mixture was diluted with ethyl acetate and washed with dilute citric acid, dilute NaHCO₃ and brine successively, then dried. Concentration followed by chromatography with ethyl acetate as the eluent gave the product as an amorphous solid(1.6 g, 70% yield). ¹ H NMR(300 MHz, CDCl₃) δ2.64(s, 3H), 3.58(m, 1H), 3.60(s, 3H), 3.76(m, 1H), 4.00(m, 1H), 4.20(s, 2H), 5.80(s, broad, 1H), 7.00(s, broad, 1H), 7.32(m, 2H), 7.44(t,J=6, 1H), 7.79(d, J=8, 2H), 7.90(d, J=6, 1H), 8.10(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 500. Found: 500.

Part D. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(s)-diaminopropionate TFA salt

An analogous procedure to that of Part K in Example 1 was applied to prepare this compound. ¹ H NMR(300 MHz, CDCl₃) δ2.80(s, 3H), 3.28(m, 1H), 3.34(s, 3H), 3.44(m, 1H), 3.96(m, 1H), 4.00(d, J=16, 1H), 4.10(d, J=16, 1H), 7.30(m, 2H), 7.44(t, J=7, 1H), 7.78(d, J=7, 1H), 8.00(d, J=8, 2H), 8.20(d, J=8, 2H), 8.50(d, J=6, 1H), 8.78(t, J=5, 1H), 9.46(s broad, 2H), 9.60(s, broad, 1H); MS(ESI) Calc. for (M+1)⁺ : 517. Found: 517.

EXAMPLE 89

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionate acid HCl salt

This compound was prepared analogously to Example 2. MS(ESI) Calc. for (M+1)+: 503. Found: 503.

EXAMPLE 96

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-N³ -Boc-(S)-2,3-diaminopropionate.

This material was synthesized analogously to the product of Part A in Example 25 from methyl N₃ -Boc-(S)-2,3-diaminopropionate HCO₂ H salt and 3,5-dimethylisoxazol-4-ylsulfonyl chloride. ¹ H NMR (300 MHz, CDCl₃) δ1.44(S, 9H), 2.40(s, 3H), 2.62(s, 3H), 3.48(m, 2H), 3.50(s, 3H), 3.98(m, 1H), 4.94(s, broad, 1H), 5.98(d, J=8, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 378. Found: 378.

Part B. Methyl N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-(S)-2,3-diaminopropionate HCl salt

This material was prepared analogously to the product of Part B in Example 25 from methyl N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-N³ -Boc-(S)-2,3-diaminopropionate. MS(ESI) Calc. for (M+1)+: 278. Found: 278(free base).

Part C. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionate

This material was prepared analogously to the product of Part J in Example 1 from 2-[2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl]acetic acid and methyl N² -(3.5-dimethylisoxazol-4-ylsulfonyl)-(S)-2,3-diaminopropionate HCl salt. ¹ H NMR(300 MHz, CDCl₃) δ2.40(s, 3H), 2.60(s 3H), 3.60(m, 1H), 3.65(s, 3H), 3.80(m, 1H), 4.10(m, 1H), 4.22(s, 2H), 6.28(d, J=8, 1H), 7.44(t, J=5, 1H), 7.80(d, J=8, 2H), 8.10(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 505. Found: 505.

Part D. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

An analogous procedure to that of Part K in Example 1 was applied to prepare this compound. ¹ H NMR(300 MHz, DMSO-d₆) δ2.34(s, 3H), 2.56(s, 3H), 3.30(m, 1H), 3.42(m, 1H). 3.48(s, 3H), 4.0(m, 1H), 4.10(d, J=16, 1H), 4.16(d, J=16, 1H), 8.00(d J=8, 2H), 8.20(d, J=8, 2H), 8.76(t, J=5, 1H); MS(ESI) Calc. for (M+1)⁺ : 522. Found: 522.

EXAMPLE 97

N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt

This compound was prepared analogously to Example 2. MS(ESI) Calc. for (M+1)⁺ : 508. Found: 508.

EXAMPLE 104

Methyl N³ -[2-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Ethyl 4-(N-triphenylmethyl)piperidinecarboxylate

A mixture of ethyl 4-piperidinecarboxylate(10 g, 63.6 mmol), triphenylmethyl chloride(17.7 g, 63.6 mmol) and triethylamine(7.0 g, 69.7 mmol) in methylene chloride(150 ml) was stirred for 16 hrs at rt, and washed with dilute citric acid, saturated NaHCO₃ and brine, and then dried. Concentration gave a powder(24 g, 95% yield). ¹ H NMR(300 MHz, CDCl₃) δ1.22(t, J=6, 3H), 1.40(m, 2H), 1.70-2.20(m, 5H), 3.10(m, 1H), 4.10(q, J=6, 2H), 7.24(m, 15H); MS(NH₃ -DCI) Calc. for (M+1)⁺ : 400. Found: 400.

Part B. 4-(N-triphenylmethyl)piperidinecarbonylhydrazine

Ethyl 4-(N-triphenylmethyl)piperidinecarboxylate(10 g, 25.1 mmol) was dissolved in hydrazine monohydrate(20 ml) and the resulting mixture was heated to reflux for 2 hrs. The excess hydrazine was removed under reduced pressure and the oily residue was pure enough for next reaction. MS(NH₃ -CI) Calc. for (M+1)⁺ : 386. Found: 386.

Part C. N-{4-(N-triphenylmethyl)piperdinecarbonyl}-N'-2-methoxycarbonylacetyl)hydrazine

This material was prepared analogously to the product of Part B in Example 1. ¹ H NMR(300 MHz, CDCl₃) δ1.40(m, 2H), 1.80(m, 2H), 2.10(m, 3H), 3.20(m, 2H), 3.40(s, 2H), 3.80(s, 3H), 7.20(m, 15H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 486. Found: 486.

Part D. Methyl 2-{2-(4-N-triphenylmethylpiperidinyl)-1.3.4-thiadiazol-5-yl}acetate

This material was prepared analogously to the product of Part C of Example 1. ¹ H NMR(300 MHz, CDCl₃) δ1.58(m, 2H), 2.10(m, 4H), 2.96(m, 1H), 3.24(m, 2H), 3.80(s, 3H), 4.20(s, 2H), 7.40(m, 15H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 484. Found: 484.

Part E. 2-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}acetic acid

This material was prepared analogously to the product of part D in Example 1. ¹ H NMR(300 MHz, DMSO-d₆) δ1.58(m, 2H), 2.10(m, 4H), 2.96(m, 1H), 3.24(m, 2H), 4.20(s, 2H), 7.20-7.60(m, 15H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 470. Found: 470.

Part F. Methyl N³ -[2-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}acetyl]-N.sup.2 -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

This material was prepared analogously to the product of part J in Example 1 from 2-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}acetic acid and methyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt. ¹ H NMR(300 MHz, CDCl₃) δ1.52(m, 2H), 2.14(m, 4H), 2.40(s, 3H), 2.98(m, 1H), 3.24(m, 2H), 3.58(m, 1H), 3.50(s, 3H), 3.68(m, 1H), 4.02(s, 2H), 4.10(m, 1H), 5.88(s, broad, 1H), 7.10-7.70(m, 19H); MS(NH₃ -DCI) Calc. for (M+NH₄)⁺ : 741. Found: 741.

Part G. Methyl N³ -[2-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Methyl N³ -[2-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N.sup.2 -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(240 mg, 0.33 mmol) was dissolved in 10% acetic acid in methanol (20 ml) and resulting solution was heated to reflux for 30 mins. After evaporation, the residue was taken up in methanol (5 ml) and TFA(0.2 ml) and purified by reversed phase HPLC to give an oil(178 mg, 90% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ1.84(m, 2H), 2.14(m, 4H), 2.36(s, 3H), 2.98(m, 1H), 3.24(m, 2H), 3.58(m, 1H), 3.50(s, 3H), 3.68(m, 1H), 4.02(s, 2H), 4.10(m, 1H), 5.88(s, broad, 1H), 7.24(m, 2H), 7.39(m, 1H), 7.41(s, 1H); MS(ESI) Calc. for (M+1)⁺ : 482. Found: 482.

EXAMPLE 133

Methyl N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. N-{4-(N-triphenylmethyl)piperdinecarbonyl}-N'-4-methoxycarbonylbutyryl)hydrazine

This material was prepared analogously to the product of Part B in Example 1 from 4-N-triphenylmethylpiperidinecarbonylhydrazine and 4-methoxycarbonylbutyryl chloride. ¹ H NMR(300 MHz, CDCl₃) δ1.40(m, 2H), 1.70=2.08(m, 5H), 2.30-2.48(m, 4H), 3.20(m, 2H), 3.66(s, 3H), 3.74(m, 1H), 7.10-7.50(m, 15H), 8.60(t, J=4, 1H), 8.86(t, J=4, 1H); MS(NH₃ -DCI) Calc. for (M+NH₄)⁺ : 531. Found: 531.

Part B. Methyl 4-{2-(4-N-triphenylmethylpiperidinyl)-1.3.4-thiadiazol-5-yl}butyrate

This material was prepared analogously to the product of Part C of Example 1. ¹ H NMR(300 MHz, CDCl₃) δ1.50(m, 2H), 2.10(m, 6H), 2.44(t, J=7, 2H), 2.94(m, 1H), 3.16(t, J=6, 2H), 3.24(m, 2H), 3.70(s, 3H), 7.10-7.50(m, 15H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 512. Found: 512.

Part C. 4-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}butyric acid

This material was prepared analogously to the product of Part D in Example 1. ¹ H NMR(300 MHz, DMSO-d₆) δ1.44(m, 2H), 2.00(m, 6H), 2.34(t, J=6, 2H), 2.96(m, 1H), 3.08(t, J=6, 2H), 3.38(s, 2H), 7.10-7.50(m, 15H), 12.20(m, 1H); MS(NH₃ -DCI) Calc. for (M+NH₄)⁺ : 498. Found: 498.

Part D. Methyl N³ -[4-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N.sup.2 -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

This material was prepared analogously to the product of Part J in Example 1 from 4-{2-(4-N-triphenylmethylpiperidinyl)-1,3,4-thiadiazol-5-yl}butyric acid and methyl N² -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate HCl salt. ¹ H NMR(300 MHz, CDCl₃) δ1.52(m, 2H), 2.10(m, 6H), 2.24(t, J=6, 2H), 2.40(s, 3H), 2.98(m, 1H), 3.16(t, J=6, 2H), 3.24(m, 2H), 3.58(s, 3H), 3.62(m, 2H), 4.02(m, 1H), 6.06(d, J=8, 1H), 6.38(t, J=6, 1H), 7.10-7.70(m, 19H); MS(NH₃ -DCI) Calc. for (M+1)⁺ : 752. Found: 752.

Part E. Methyl N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

This similar procedure as in Part G of Example 133 was adopted to prepare this compound. ¹ H NMR(300 MHz, DMSO-d₆) δ1.80(m, 2H), 2.14(m, 6H), 2.28(t, J=6, 2H), 2.38(s, 3H), 2.98(m, 1H), 3.16(t, J=6, 2H), 3.24(m, 2H), 3.58(s, 3H), 3.62(m, 2H), 4.02(m, 1H), 6.06(d, J=8, 1H), 6.38(t, J=6, 1H), 7.18(m, 2H), 7.30(m, 1H), 7.32(s, 1H); MS(ESI) Calc. for (M+1)⁺ : 510. Found: 510.

EXAMPLE 134

N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt

Methyl N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt(300 mg, 0.47 mmol) was dissolved in aqueous THF(15 ml) containing methanol(5 ml) and lithium hydroxide monohydrate(42 mg, 1 mmol). After stirring at rt for 12 hrs, the mixture was evaporated to dryness and the residue was taken up in methanol(5 ml) containing TFA(0.2 ml) and purified by reversed phase HPLC to afford an oil(250 mg, 86%). MS(ESI) Calc. for (M+1)⁺ : 496. Found: 496.

EXAMPLE 144

Methyl N³ -[2-{2-(4-N,N'-di(trifluoroethyl)amidinophenyl)-1,3,4-thiadiazol -5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

Dry HCl gas was bubled through a solution of Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(400 mg, 0.80 mmol) in dry CHCl₃ containing anhydrous methanol (38 mg, 1.2 mmol), cooled with salt ice-water bath, at 0 C. for 5 hrs. The resulting solution was then kept at 0 C. for 6 hrs and at 15 C. for 12 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol(7 ml) followed by addition of trifluoroethylamine(200 mg, 2 mmol). After stirring at rt for 4 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give a white amorphous solid(305 mg, 56% yield). Further purification by reversed phase HPLC using a mixture of water and 0.1% TFA in acetonitrile gave the TFA salt. ¹ H NMR(300 MHz, DMSO-d₆) δ2.36(S, 3H), 3.24(m, 1H), 3.40(s, 3H), 3.44(m, 1H), 3.90-4.10(m, 7H), 7.20(m, 2H), 7.26(d, J=8, 2H), 7.34(m, 1H), 7.36(s, 1H), 7.42(d, J=8, 2H), 7.70(d, J=6, 1H), 8.20(m, 1H), 8.70(m, 1H); MS(ESI) Calc. for (M+1)⁺ : 681. Found: 681.

EXAMPLE 145

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. 4-Nitrobenzoylhydrazine

This material was prepared analogously to 4-cyanobenzoylhydrazine from 4-nitrobenzene and hydrazine monohydrate. ¹ H NMR(300 MHz, CDCl₃) δ4.16(s, 2H), 7.40(s, broad, 1H), 7.94(d, J=8, 2H), 8.34(d,J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 182. Found: 182.

Part B. N-(4-nitrobenzoyl)-N'-(2-methoxycarbonylacetyl)hydrazine

This material was prepared analogously to the product of Part B in Example 1. ¹ H NMR(300 MHz, DMSO-d₆) δ3.40(s, 2H), 3.70(s, 3H), 8.10(d, J=8, 2H), 8.40(d, J=8, 2H), 10.40(s, 1H), 10.90(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 282. Found: 282.

Part C. Methyl 2-{2-(4-nitrophenyl)-1,3,4-thiadiazol-5-yl}acetate

This compound was prepared analogously to the product of Part C in Example 1. ¹ H NMR(300 MHz, CDCl₃) δ3.84(s, 3H), 4.30(s, 2H), 8.20(d, J=8, 2H), 8.40(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 280. Found: 280.

Part D. 2-{2-(4-nitrophenyl)-1,3,4-thiadiazol-5-yl}acetic acid

This acid was prepared analogously to the product of Part D in Example 1. ¹ H NMR(300 MHz, DMSO-d₆) δ4.40(s, 2H), 8.30(d, J=8, 2H), 8.40(d, J=8, 2H), 13.20(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 266. Found: 266.

Part E. Methyl N³ -[2-{2-(4-nitrophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsufonyl)-2,3-(S)-diaminopropionate

This compound was prepared analogously to the product of Part J in Example 1. ¹ H NMR(300 MHz, CDCl₃) δ2.40(s, 3H), 3.58(s, 3H), 3.60(m, 1H), 3.80(m, 1H), 4.10(m, 1H), 4.22(s, 2H), 5.92(d, J=6, 1H), 7.26(s, broad, 1H), 7.38(d, J=5, 2H), 7.62(m, 2H), 8.16(d, J=8, 2H), 7.38(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 520. Found: 520.

Part F. Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsufonyl)-2,3-(S)-diaminopropionate

The nitro compound obtained in Part D(200 mg, 0.4 mmol) dissolved in ethyl acetate containing 10% Pd/C(20 mg) was hydrogenated in a shaking bottle overnight under a hydrogen pressure of 50 psi. Filtration through Celite and concentration gave an oil(190 mg, 100% yield). 1H NMR(300 MHz, CDCl₃) δ2.40(s, 3H), 3.58(s, 3H), 3.60(m, 2H), 4.02(s, 2H), 4.10(m, 1H), 5.90(d, J=8, 1H), 6.70(d, J=8, 2H), 7.36(m, 3H), 7.62(m, 2H), 8.78(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 590. Found: 590.

Part G. N,N'-Bis-tert-butoxycarbonylthiourea

This material was prepared according to the method of Iwanowicz, et al (Synthetic Commun. 1993, 23, 1443).

Part H. Methyl N³ -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-thiadiazol -5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

A mixture of N,N'-bis-tert-butoxycarbonylthiourea(130 mg, 0.26 mmol), HgCl₂ (110 mg, 0.4 mmol) and prydine(62 mg, 0.80 mmol) in dry DMF(2 ml), cooled with ice-water, was stirred for 15 mins followed by addition of Methyl N³ -[2-{2-(4-amminophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate (130 mg, 0.26 mmol). Stirring was continued for 24 hrs. After filtration through Celite, the filtrate was diluted with ethyl acetate and washed with brine, and then dried. The residue obtained after concentration was chromatographed over silica gel to give an amorphous solid(150 mg, 78% yield). ¹ H NMR(300 MHz, CDCl₃) δ1.54(s, 9H), 1.58(s, 9H), 2.40(s, 3H), 3.58(S, 3H), 3.42(m, 2H), 4.08(s, 2H), 4.10(m, 1H), 5.80(s, broad, 1H), 7.20(s, broad, 1H), 7.40(d, J=7, 2H), 7.64(m, 2H), 7.78(d, J=8, 2H), 7.90(d, J=8, 2H), 10.60(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 732. Found:732.

Part I. Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

A solution of Methyl N³ -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsufonyl)-2,3-(S)-diaminopropionate (100 mg, 0.14 mmol) in methylene chloride(3 ml) containing TFA(1 ml) was stirred at rt for 2 hrs. After evaporation, the residue was taken un in methanol(4 ml) and purified by HPLC to afford an oily product(75 mg, 85% yield). MS(ESI) Calc. for (M+1)⁺ : 532. Found: 532(free base).

EXAMPLE 146

N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt

This material was prepared analogously to Example 144. MS(ESI) Calc. for (M+1)⁺ : 518. Found: 518.

EXAMPLE 157

Methyl N³ -[2-{2-(4-N-hydroxyamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt

A mixture of methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(s)-diaminopropionate(500 mg, 1 mmol), hydroxyamine hydrogen chloride (83 mg, 1.2 mmol) and triethylamine(120 mg, 1.2 mmol) in methanol(10 ml) was stirred at rt for 24 hrs. The solid was collected by filtration(430 mg, 80% yield). Further purification by reversed phase HPLC gave the TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ2.40(s, 3H), 3.58(s, 3H), 3.62(m, 2H), 4.10(m, 3H), 4.94(1, 1H), 5.82(s, broad, 1H), 7.10(s, broad, 1H), 7.40(d, J=6, 2H), 7.64(m, 2H), 7.74(d, J=8, 2H), 7.96(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 533. Found: 533.

EXAMPLE 170

Methyl N³ -[2-{2-(4-amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate

To a mixture of methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-yl}acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate(200 mg, 0.4 mmol) and potassium bicarbonate(220 mg, 1.6 mmol) in DMSO(4 ml), cooled with ice-water, was added hydrogen peroxide(30%, 1 ml). After stirring at rt for 2 hrs, the reaction mixture was diluted with ethyl acetate and worked up as usual. The residue obtained after concentration was chromatographed over silica gel to give a powder solid(135 mg, 65% yield). ¹ H NMR(300 MHz, CDCl₃) δ2.38(s, 3H), 3.20(m, 1H), 3.36(s, 3H), 3.40(m, 1H), 4.00(m, 3H), 7.40(m, 2H), 7.52(m, 3H), 8.02(d, J=8, 2H), 8.08(d, J=8, 2H), 8.14(s, 1H), 8.42(d, J=8, 1H), 8.60(t, J=5, 1H); MS(ESI) Calc. for (M+1)⁺ : 518. Found: 518.

EXAMPLE 171

N³ -[2-{2-(4-Amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid

This material was prepared analogously to Example 2. MS(ESI) Calc. for (M+1)⁺ : 504. Found: 504.

EXAMPLE 192

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

Part A. Benzyldithiocarbhydrazide

This compound was prepared according to the procedure of Busch and Starke (J. Prakt. Chem. 1916, 93, 49). ¹ H NMR(300 MHz, CDCl₃) δ4.10(s, 1H), 4.54(s, 1H), 4.70(s, 1H), 4.20-4.50(m, 5H).

Part B. Benzyl 3-(4-cyanobenzoyl)dithiocarbazinate

A mixture of 4-cyanobenzoyl chloride(3.31 g, 20 mmol) and benzyldithiocarbhydride(3.96 g, 20 mmol) in pyridine(20 ml) was heated at 80-90 C. for 1 hr, and then poured into ice water(140 ml) containing 15 ml of conc. H2SO4, extracted with ethyl acetate. The extract was washed with water (20 ml×2) and dried. After evaporation of the solvent, the solid was triturated with anhydrous ether and pumped to give the product as a white powder(4 g, 61% yield). ¹ H NMR(300 MHz, CDCl₃) δ4.58(s, 2H), 7.30-7.40(m, 5H), 7.80(d, J=8, 2H), 7.98(d, J=8, 2-H), 10.60(s, 2H); MS(NH₃ -DCI) Calc for (M+NH₄)⁺ : 345. Found: 345.

Part C. 2-(4-Cyanophenyl)-5-benzylthio-1,3,4-thiadiazole

A mixture of benzyl 3-(4-cyanobenzoyl)dithiocarbazinate(1 g, 3.1 mmol) and 4-methylbenzenesulfonyl chloride(100 mg) in 25 ml of benzene was refluxed for 3 hrs. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to afford a white solid(800 mg, 85% yield). ¹ H NMR(300 MHz, CDCl₃) δ4.62(s, 2H), 7.34(m, 3H), 7.48(d, J=6, 2H), 7.76(d, J=8, 2H), 8.00(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 310. Found: 310.

Part D. 2-(4-Cyanophenyl)-5-benzylsulfonyl-1,3,4-thiadiazole

To a solution of 2-(4-Cyanophenyl)-5-benzylthio-1,3,4-thiadiazole(560 mg, 1.81 mmol) in acetic acid (7 ml) was slowly added an aqueous solution of KMnO₄ (3%, 40 ml). After addition, the resulting mixture was heated at 60 C. for 2 hrs, and then poured into water. After decolorization with Na₂ S₂ O₃, the aqueous solution was filtered and the solid portion was recrystallized from ethanol to give a white solid(510 mg, 83% yield). ¹ H NMR(300 MHz, CDCl₃) δ4.84(s, 2H), 7.36(m, 5H), 7.82(d, J=8, 2H), 8.08(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 342. Found: 342.

Part E. 2-{2-(4-Cyanophenyl)-1,3,4-thiadiazol-5-ylthio}acetic acid

A mixture of 2-(4-cyanophenyl)-5-benzylsulfonyl-1,3,4-thiadiazole(407 mg, 1.2 mmol), mercaptoacetic acid(110 mg, 1.2 mmol) and triethylamine(120 mg, 1.2 mmol) in ethanol(20 ml) was stirred at rt overnight. The solvent was evaporated and the residue was triturated with water, dried to afforded 290 mg of the product (88% yield). ¹ H NMR(300 MHz, CDCl₃) δ4.02(s, 2H), 8.00(d, J=8, 2H), 8.10(d, J=8, 2H); MS(NH₃ -DCI) Calc. for (M+NH₄)⁺ : 295. Found: 295.

Part F. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A similar procedure to Part J in Example 1 was adopted to prepare this compound from 2-{2-(4-Cyanophenyl)-1,3,4-thiadiazol-5-ylthio}acetic acid and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=7, 3H), 1.36(m, 2H), 1.58(m, 2H), 3.54(m, 1H), 3.74(s, 3H), 3.76(m, 1H), 3.90-4.10(m, 3H), 4.42(s, broad, 1H), 5,60(d, J=6, 1H), 7.78(d, J=8, 2H), 8.00(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 478. Found: 478.

Part G. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

Dry HCl gas was bubled through a solution of Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate(260 mg, 0.55 mmol) in dry CHCl₃ containing anhydrous methanol(35 mg, 1.1 mmol), cooled with salt ice-water bath, at 0 C. for 5 hrs. The resulting solution was then kept at 0 C. for 6 hrs and at 15 C. for 12 hrs. The flammable portion was removed and the residue was dissolved in aqueous methanol(75%, 5 ml) containing ammonium chloride (110 mg, 2.2 mmol). After stirring at reflux for 2 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give an amorphous solid(180 mg, 62% yield). ¹ H NMR(300 MHz, CDCl₃) δ0.86(t, J=7, 3H), 1.30(m, 2H), 1.50(m, 2H), 3.50(m, 1H), 3.60(s, 3H), 3.90(t, J=8, 1H), 4.18(m, 3H), 8.04(d, J=8, 2H), 8.14(d, J=8, 2H), 8.66(t, J=5, 1H);MS(ESI) Calc. for (M+1)⁺ : 495. Found: 495(free base).

EXAMPLE 193

N³ -[2-{2-(4-Amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt

A similar procedure to Example 134 was adopted to prepare this acid from Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate HCl salt. MS(ESI) Calc. for (M+1)⁺ : 481. Found: 481.

EXAMPLE 222

Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl 4-tert-butoxycarbonylaminobenzoate

To a solution of methyl 4-aminobenzoate(5.2 g, 34 mmol) and (Boc)₂ O(7.4 g 34 mmol) in methylene chloride(50 ml), cooled with ice water, was added one equivalent DMAP. After stirring overnight, the mixture was diluted with additional 50 ml of methylene chloride and washed with dilute citric acid, saturated NaHCO₃ and brine, dried. Removal of the solvent gave 4.5 g of the product. ¹ H NMR(300 MHz, CDCl₃) δ1.54(s, 9H), 3.88(s, 3H), 7.44(d, J=8, 2H), 7.98(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 252. Found: 252.

Part B. 4-tert-Butoxycarbonylaminobenzoylhydrazine

A mixture of Methyl 4-tert-butoxycarbonylaminobenzoate (500 mg, 2 mmol) and hydrazine monohydrate(3 ml) was heated to reflux for 1 hr. The excess hydrazine was removed under reduced pressure and the residue was recrystallized from methanol to a solid(420 mg, 84% yield). ¹ H NMR(300 MHz, CDCl₃) δ1.56(s, 9H), 6.70(s, 2H), 7.35(s, 1H), 7.44(d, J=8, 2H), 7.70(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 252. Found: 252.

Part C. 2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetic acid

A mixture of 4-tert-Butoxycarbonylaminobenzoylhydrazine(820 mg. 3.3 mmol) and potassium hydroxide(217 mg, 3.3 mmol) in ethanol(95%, 20 ml) was stirred till all potassium hydroxide was dissolved. Carbon disulfide(280 mg, 3.6 mmol) was then introduced, and the solution gradually became pale yellow and some precipitate appeared. After stirring at reflux for 10 hrs, mercaptoacetic acid(460 mg, 3.3 mmol) was added and stirring was continued for 12 hrs at rt and 2 hrs at reflux. The solvent was removed and the residue was chromatographed over silica gel, affording 840 mg of the product(73% yield). ¹ H NMR(300 NHz, DMSO-d₆) δ1.50(s, 9H), 4.20(s, 2H), 7.68(d, J=8, 2H), 7.88(d, J=8, 2H), 9.82(s, 1H); MS(NH₃ -DCI) Calc for (M+1)⁺ : 352. Found: 352.

Part D. Methyl N³ -[2-{2-(4-tert butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A similar coupling reaction procedure to Part J in Example 1 was adopted to prepare this compound from 2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetic acid and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6, 3H), 1.38(m, 2H), 1.56(s, 9H), 1.58(m, 2H), 3.70(m, 2H), 3.74(s, 3H), 3.84(d, J=16, 1H), 3.92(d, J=16, 1H), 4.02(m, 3H), 4.42(s, broad, 1H), 5,62(s, broad, 1H), 6.68(s, s, 1H), 7.56(d, J=8, 2H), 7.94(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 552. Found: 552.

Part E Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

A similar procedure to Part H in Example 145 was adopted to prepare this material from Methyl N³ -[2-{2-(4-tert-butoxycarbonylamino phenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate. MS(ESI) Calc. for (M+1)⁺ : 452. Found: 452.

EXAMPLE 242

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N3-[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N2-(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A mixture of N,N'-bis-tert-butoxycarbonylthiourea (85 mg, 0.31 mmol), HgCl₂ (84 mg, 0.31 mmol) and prydine(25 mg, 0.31 mmol) in dry DMF(1 ml), cooled with ice-water, was stirred for 15 mins followed by addition of Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate (70 mg, 0.16 mmol). Stirring was continued for 24 hrs. After filtration through Celite, the filtrate was diluted with ethyl acetate and washed with brine, and then dried. The residue obtained after concentration was chromatographed over silica gel to give an amorphous solid(87 mg, 81% yield). ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6,3H), 1.38(m, 2H), 1.54(s, 9H), 1.58(s, 9H), 1.60(m, 2H), 3.70(m, 2H), 3.72(s, 3H), 3.84(d, J=16, 1H), 3.92(d, J=16, 1H), 4.04(m, 3H), 4.44(s, broad 1H), 5.64(d, J=6, 1H), 7.46(t, J=4, 1H), 7.82(d, J=8, 2H), 7.96(d, J=8, 2H), 10.60(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 694. Found: 694.

Part B. Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

A solution of Methyl N³ -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate (70 mg, 0.10 mmol) in methylene chloride(3 ml) containing TFA(1 ml) was stirred at rt for 2 hrs. After evaporation, the residue was taken up in methanol(4 ml) and purified by HPLC to afford an oily product(45 mg, 90% yield). MS(ESI) Calc. for (M+1)⁺ : 494. Found: 494(free base).

EXAMPLE 258

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diamino propionate HCl salt

Part A. 2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-ylthio}acetic acid

A mixture of 4-cyanobenzoylhydrazine(3.22 g. 20 mmol) and potassium hydroxide(1.32 g, 20 mmol) in ethanol(95%, 100 ml) was stirred till all potassium hydroxide was dissolved. Carbon disulfide(1.67 g, 22 mmol) was then introduced. After stirring at reflux for 24 hrs, mercaptoacetic acid(2.78 g, 20 mmol) was added and stirring was continued for 16 hrs at rt. The solvent was removed and the residue was chromatographed over silica gel, affording 2.9 g of the product(56% yield). ¹ H NMR(300 NHz, DMSO-d₆) δ4.10(s, 2H), 7.08(d, J=8, 2H), 7.16(d, J=8, 2H); MS(NH₃ -DCI) Calc for (M+1)⁺ : 262. Found: 262.

Part B. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A similar coupling reaction procedure to Part J in Example 1 was adopted to prepare this compound from 2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-ylthio}acetic acid and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6, 3H), 1.38(m, 2H), 1.58(m, 2H), 3.70(m,2H), 3.74(s, 3H), 3.90(d, J=16, 1H), 3.96(d, J=16, 1H), 4.02(m, 3H), 4.42(m, 1H), 5,60(d, J=5, 1H), 7.82(d, J=8, 2H), 7.16(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 462. Found: 462.

Part C. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N² -(n-butyloxycarbonyl-2,3-(S)-diaminopropionate HCl salt

Dry HCl gas was bubled through a solution of Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(s)-diaminopropionate(250 mg, 0.54 mmol) in dry CHCl₃ (8 ml) containing anhydrous methanol(21 mg, 0.65 mmol), cooled with salt ice-water bath, at 0 C. for 6 hrs. The resulting solution was then kept at 0 C. for 12 hrs and at 15 C. for 5 hrs. The flammable portion was removed and the residue was dissolved in aqueous methanol(75%, 5 ml) containing ammonium chloride(110 mg, 2.1 mmol). After stirring at reflux for 3 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give an amorphous solid(83 mg, 32% yield). ¹ H NMR(300 MHz, DMSO-d₆) δ0.90(t, J=7, 3H), 1.34(m, 2H), 1.52(m, 2H), 3.48(m, 2H), 3.60(s, 3H), 3.78(d, J=16, 1H), 3.92(d, J=16, 1H), 4.18(m, 3H), 7.98(d, J=8, 2H), 8.16(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 478. Found: 478(free base).

EXAMPLE 290

Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

Part A. Methyl 2-{2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl}acetate

A mixture of N-(4-nitrobenzoyl)-N'-methoxycarbonylacetylhydrazine(the product of part B in Example 145)(1 g, 3.6 mmol) and phosphorus oxychloride(3.3 ml) in dry acetonitrile was heated to reflux for 2 hrs. The solvent was evaporated and the oily residue was taken up in ethyl acetate and worked up as usual. Chromatography afforded 950 mg of the product(930 mg, 100% yield). ¹ H NMR(300 MHz, CDCl₃) δ3.80(s, 3H), 4.10(s, 2H), 8.26(d, J=8, 2H), 8.40(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 264. Found: 264.

Part B. 2-{2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl}acetic acid

A similar procedure to Part D of Example 1 was applied to prepare this acid. ¹ H NMR(300 MHz, DMSO-d₆) δ4.10(s, 2H), 8.26(d, J=8, 2H), 8.44(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 250. Found: 250.

Part C. Methyl N³ -[2-{2-(4-nitrophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A similar coupling reaction procedure to Part J of Example 1 was applied to prepare this compound from the acid of Part B and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6, 3H), 1.36(m, 2H), 1.58(m, 2H), 3.70(m, 2H), 3.80(s, 3H), 4.00(s, 2H), 4.06(m, 3H). 4.90(s, broad, 1H), 5.74(d, J=6, 1H), 8.26(d, J=8, 2H), 8.40(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 450. Found: 450.

Part D. Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

The nitro compound obtained in Part C(85 mg, 0.19 mmol) dissolved in ethyl acetate(20 ml) containing 10% Pd/C(10 mg) was hydrogenated in a shaking bottle overnight under a hydrogen pressure of 50 psi. Filtration through Celite and concentration gave an oil(81 mg, 100% yield). ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6, 3H), 1.38(m, 2H), 1.60(m, 2H), 3.78(m, 2H), 3.80(s, 3H), 3.90(s, 2H), 4.06(m, 3H), 4.50(s,broad, 1H), 5.70(d, J=6, 1H), 6.76(d, J=8, 2H), 7.80(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 430. Found: 430.

EXAMPLE 318

Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N-² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl 2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-yl}acetate

This material was anologously prepared to the product of Part A of Example 290 from 4-cyanobenzoylhydrazine(the product of Part A of Example 1). ¹ H NMR(300 MHz, CDCl₃) δ3.80(s, 3H), 4.10(s, 2H), 7.80(d, J=8, 2H), 8.20(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 244. Found: 244.

Part B. 2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-yl}acetic acid

A similar procedure to Part D of Example 1 was applied to prepare this acid. ¹ H NMR(300 MHz, DMSO-d₆) δ4.20(s, 2H), 8.08(d, J=8, 2H), 8.18(d, J=8, 2H); MS(NH₃ -DCI) Calc. for (M+1)⁺ : 230. Found: 230.

Part C. Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A similar coupling reaction procedure to Part J of Example 1 was applied to prepare this compound from the acid obtained from Part B and methyl N² -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt. ¹ H NMR(300 MHz, CDCl₃) δ0.94(t, J=6, 3H), 1.36(m, 2H), 1.58(m, 2H), 3.68(m, 2H), 3.80(s, 3H), 3.98(s, 2H), 4.06(m, 3H). 4.46(s, broad, 1H), 5.68(d, J=6, 1H), 7.80(d, J=8, 2H), 8.20(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 430. Found: 430.

Part D. Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Dry HCl gas was bubled through a solution of Methyl N³ -[2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate(750 mg, 1.75 mmol) in dry CHCl₃ (15 ml) containing anhydrous methanol (76 mg, 2.1 mmol), cooled with salt ice-water bath, at 0 C. for 5 hrs. The resulting solution was then kept at 0 C. for 12 hrs and at 15 C. for 5 hrs. The flammable portion was removed and the residue was dissolved in anhydrous methanol(12 ml) followed by addition of ammonium bicarbonate(504 mg, 5.25 mmol). After stirring at rt for 4 hrs, the mixture was concentrated and purified by flush chromatography over silica gel using a mixture of methylene chloride and methanol to give an amorphous solid(273 mg, 35% yield). Further purification gave the TFA salt. ¹ H NMR(300 MHz, DMSO-d₆) δ0.90(t, J=6, 3H), 1.32(m, 2H), 1.58(m, 2H), 3.40(m, 2H), 3.60(s, 3H), 3.94(t, J=6, 2H), 4.01(m, 1H), 4.20(s, 2H), 7.56(s, broad, 1H), 7.60(d,J=8, 2H), 8.08(d, J=8, 2H), 8.70(m, 1H), 9.40(s, 1H), 9.60(s, 2H); MS(ESI) Calc. for (M+1)⁺ : 447. Found: 447.

EXAMPLE 335

Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N³ -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate

A mixture of N,N'-bis-tert-butoxycarbonylthiourea(92 mg, 0.33 mmol), HgCl₂ (91 mg, 0.33 mmol) and prydine(26 mg, 0.33 mmol) in dry DMF(1 ml), cooled with ice-water, was stirred for 15 mins followed by addition of Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate(70 mg, 0.17 mmol). Stirring was continued for 24 hrs. After filtration through Celite, the filtrate was diluted with ethyl acetate and washed with brine, and then dried. The residue obtained after concentration was chromatographed over silica gel to give an amorphous solid(95 mg, 86% yield). ¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=6,3H), 1.38(m, 2H), 1.54(s, 9H), 1.58(s, 9H), 1.60(m, 2H), 3.74(m, 2H), 3.78(s, 3H), 3.94(s, 2H), 4.04(m, 3H), 4.44(s, broad, 1H), 5.68(d, J=6, 1H), 7.52(t, J=4, 1H), 7.82(d, J=8, 2H), 7.02(d, J=8, 2H), 10.65(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 662. Found:662.

Part B. Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

A solution of Methyl N³ -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-yl}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate(70 mg, 0.10 mmol) in methylene chloride(3 ml) containing TFA(1 ml) was stirred at rt for 2 hrs. After evaporation, the residue was taken up in methanol(4 ml) and purified by HPLC to afford an oily product(46 mg, 95% yield). MS(ESI) Calc. for (M+1)⁺ : 462. Found: 462(free base).

EXAMPLE 353

Methyl N-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine

Part A. Methyl N-(2-chloroacetyl)glycine

This material was prepared according to the procedure of Birnbaum et al (J. Bio. Chem. 1952, 194, 455) from glycine hydrogen chloride and chloroacetyl anhydride. ¹ H NMR(300 MHz, CDCl₃) δ3.80(s, 3H), 4.08(d, J=8, 2H), 4.12(s, 2H), 7.06(s broad, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 167. Found: 167.

Part B. Methyl N-[2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]glycine

A mixture of 4-tert-Butoxycarbonylaminobenzoylhydrazine(820 mg. 3.3 mmol) and potassium hydroxide(217 mg, 3.3 mmol) in ethanol(95%, 20 ml) was stirred till all potassium hydroxide was dissolved. Carbon disulfide(280 mg, 3.6 mmol) was then introduced, and the solution gradually became pale yellow and some precipitate appeared. After stirring at reflux for 10 hrs, Methyl N-(2-chloroacetyl)glycine (4601 mg, 3.6 mmol) was added and stirring was continued for 20 hrs at reflux. The solvent was removed and the residue was worked up as usual, followed by chromatography over silica gel, affording 900 mg of the product(67% yield). ¹ H NMR(300 NHz, DMSO-d₆) δ1.56(s, 9H), 3.74(s, 3H), 3.96(s, 2H), 4.08(d, J=6, 2H), 6.68(s, 1H), 7.52(d, J=8, 2H), 7.96(d, J=8, 2H); MS(NH₃ -CI) Calc for (M+1)⁺ : 423. Found:423.

Part C Methyl N-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]glycine

A solution of Methyl N-[2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]glycine(200 mg, 0.47 mmol) in methylene chloride(5 ml) containing TFA(1.5 ml) was stirred at rt for 2 hrs. After evaporation, the residue was taken up in CH₂ Cl₂ and washed with saturated NaHCO₃ and brine, dried. Removal of the solvent gave a solid which was recrystallized from ethanol to afford 100 mg of the product(66%). ¹ H NMR(300 MHz, CDCl₃) δ3.74(s, 3H), 3.94(s, 2H), 4.08(d, J=6, 3H), 6.74(d, J=8, 2H), 7.60(s, broad, 1H), 7.80(J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 323. Found: 323.

EXAMPLE 385

Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine TFA salt

The same procedures as in Example 242 were adopted to prepare this material.

Part A. Methyl N-[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]glycine

¹ H NMR(300 MHz, CDCl₃) δ1.54(s, 9H), 1.58(s, 9H), 3.76(s, 3H), 3.98(s, 2H), 4.06(d, J=6, 2H), 7.34(t, J=5, 1H), 7.82(d, J=8, 2H), 7.98(d, J=8, 2H), 10.65(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 565. Found: 565.

Part B. Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-glycine TFA salt

MS(ESI) Calc. for (M+1)⁺ : 365. Found: 365(free base).

EXAMPLE 392

Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine TFA salt

Part A. Methyl N-2-chloroacetyl-(S)-phenylalanine

To a mixture of (s)-phenylalanine methyl ester hydrogen chloride(2.15 g, 10 mmol) and triethylamine(2.22 g, 22 mmol) in methylene chloride cooled at -10 C. with dry ice was added chloroacetic chloride(1.15 g, 10 mmol) at such a rate that the inner temperature of the mixture was kept below -5 C. After addition, the mixture was stirred at 10 C. for additional 30 mins and then at rt for 2 hrs. Work-up as usual followed by chromatography gave 2.4 g of the product (94% yield). ¹ H NMR(300 MHz, CDCl₃) δ3.14(dd, J=16 and 4, 1H), 3.18(dd, J=16 and 4, 1H), 3.76(s, 3H), 4.04(s, 2H), 4.88(m, 1H), 6.98(s, broad, 1H), 7.10-7.30(m, 5H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 256. Found: 256.

Part B. Methyl N-[2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-(S)-phenylalanine

A similar procedure to Part B of Example 30 was adopted to prepare this material from 4-tert-butoxycarbonylaminobenzoylhydrazine and methyl N-(2-chloroacetyl)-(s)-phenylalanine. ¹ H NMR (300 NHz, CDCl₃) δ1.56(s, 9H), 3.06(dd, J=16 and 4, 1H), 3.20(dd, J=16 and 4, 1H), 3.74(s, 3H), 3.82(d, J=16, 1H), 3.94(d, J=16, 1H), 4.88(m, 1H), 6.78(s, 1H), 7.02-7.18(m, 5H), 7.40(d, J=6, 1H), 7.54(d, J=8, 2H), 7.92(d, J=8, 2H); MS(NH₃ -CI) Calc for (M+1)⁺ : 513. Found:513.

Part C Methyl N-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-(S)-phenylanaline

A similar procedure to Part C of Example 30 was adopted to prepare this material. ¹ H NMR(300 MHz, CDCl₃) δ3.04(dd, J=16 and 4, 1H), 3.20(dd, J=16 and 4, 1H), 3.70(s, 3H), 3.80(d, J=16, 1H), 3.94(d, J=16, 1H), 4.86(m, 1H), 6.76(d, J=8, 2H), 7.04-7.20(m, 5H), 7.44(d, J=6, 1H), 7.78(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 413. Found: 413.

Part D. Methyl N-[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-(S)-phenylalanine

A similar procedure to Part A of Example 25 was adopted to prepare this compound. ¹ H NMR(300 MHz, CDCl₃) δ1.54(s, 9H), 1.58(s, 9H), 3.04(dd, J=16 and 4, 1H), 3.20(dd, J=16 and 4, 1H), 3.70(s, 3H), 3.80(d, J=16, 1H), 3.94(d, J=16, 1H), 4.86(m, 1H), 7.04-7.20(m, 5H), 7.40(d, J=6, 1H), 7.84(d, J=8, 2H), 7.96(d, J=8, 2H), 10.65(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 655. Found: 655.

Part E. Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-(S)-phenylalanine TFA salt

A similar procedure to Part B of Example 242 was adopted to prepare this compound.

MS(ESI) Calc. for (M+1)⁺ : 455. Found: 455(free base).

EXAMPLE 399

Ethyl N-[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine HCl salt

Part A. Methyl N-[2-{2-(4-cyanophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine HCl salt

A similar procedure to Part B of Example 353 was adopted to prepare this compound from 4-cyanobenzoylhydrazine and methyl N-(2-chloroacetyl)-(s)-phenylalanine. ¹ H NMR(300 MHz, CDCl₃) δ1.2(t, J=8, 3H), 3.04(dd, J=16 and 6, 1H), 3.20(dd, J=16 and 6, 1H), 3.88(d, J=16, 1H), 4.00(d, J=16, 1H), 4.18(q, J=8, 2H), 4.86(m, 1H), 7.04-7.24(m, 5H), 7.82(d, J=8, 2H), 8.14(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 423. Found: 423.

Part B. Ethyl N-[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine HCl salt

A similar procedure to Part C of Example 258 was adopted to prepare this material. ¹ H NMR(300 MHz, DMSO-d₆) δ1.24(t, J=8, 3H), 3.06(dd, J=16 and 6, 1H), 3.22(dd, J=16 and 6, 1H), 3.88(d, J=16, 1H), 4.00(d, J=16, 1H), 4.18(q, J=8, 2H), 4.86(m, 1H), 7.02-7.18(m, 5H), 7.90(d, J=8, 2H), 8.20(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 454. Found: 454.

EXAMPLE 404

Methyl N2-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N3-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

Part A. Methyl N² -Cbz-N³ -n-butyloxycarbonyl-(S)-2,3-diaminopropionate.

To a mixture of methyl N² -Cbz-(S)-2,3-diaminopropionate HCl salt (1 g, 3.5 mmol) and NaHCO₃ (700 mg, 8.4 mmol) in 6 mL water and 6 mL THF cooled in an ice bath was added slowly butyl chloroformate (4.2 mmol, 0.53 mL) over 15 min. After stirring for 1 hour, ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO₃ and brine, dried (MgSO₄), and concentrated to give 1.2 g (100%) oily product. ¹ H NMR (300 MHz, CDCl₃) δ0.90(t, J=8, 3H), 1.38(m, 2H), 1.58(m, 2H), 3.60(m, 2H), 3.78(s, 3H), 4.04(t, J=8, 2H), 4.42(m, 1H), 4.98(s, broad, 1H), 5.14(s, 2H), 5.80(d, J=6, 1H), 7.38(m, 5H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 353. Found: 353.

Part B. Methyl N³ -n-butyloxycarbonyl-(S)-2,3-diaminopropionate HCO₂ H salt.

A mixture of methyl N² -Cbz-N³ -n-butoxycarbonyl-(S)-2,3-diaminopropionate. (3.4 mmol, 1.3 g), formic acid (10.2 mmol, 0.38 mL) and 10% Pd/C (130 mg) in 20 mL methanol was stirred at room temperature for 1 hour and filtered through a celite. The filtrate was concentrated to give 0.75 g (100%) oily product. ¹ H NMR (300 MHz, DMSO-d₆) δ0.86(t, J=8, 3H), 1.32(m, 2H), 1.50(m, 2H), 3.19(m, 2H), 3.44(t, J=6, 1H), 3.60(s, 3H), 3.92(t, J=8, 2H), 7.18(t, J=4, 1H), 8.20(s, 2H).

Part C. Methyl N² -[2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

The same coupling reaction conditions as Part J of Example 1 were adopted to prepare the compound from 2-{2-(4-tert-butoxycarbonylaminophenyl)-1,3,4-oxadiazol-5-ylthio}acetic acid and Methyl N³ -n-butyloxycarbonyl-(S)-2,3-diaminopropionate HCO2H salt. ¹ H NMR(300 MHz, CDCl₃) δ0.92(t, J=8, 3H), 1.38(m, 2H), 1.58(m, 2H), 1.60(s, 9H), 3.64(m, 2H), 3.80(s, 3H), 4.08(t, J=8, 2H), 4.62(m, 1H), 5.20(t, J=6, 1H), 7.50(d, J=8, 2H), 7.70(d, J=6, 1H), 7.96(d, J=8, 2H), 8.24(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 552. Found: 552.

Part D. Methyl N² -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt

A similar procedure to Part C of Example 353 was adopted to prepare this material. MS(ESI) Calc. for (M+1)⁺ : 452. Found: 452.

EXAMPLE 422

Methyl N² -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

The same procedures as in Example 242 were adopted to prepare this material from Methyl N² -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate.

Part A. Methyl N² -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

¹ H NMR(300 MHz, CDCl₃) δ0.90(t, J=8, 3H), 1.32(m, 2H), 1.54(s, 9H), 1.58(s, 9H), 1.60(m, 2H), 3.64(m, 2H), 3.78(s, 3H), 3.98(t,J=8, 2H), 4.62(s, 1H), 5.20(t, J=6, 1H), 7.70(d, J=6, 1H), 7.82(d, J=8, 2H), 7.98(d, J=8, 2H), 10.62(s, 1H), 11.65(s, 1H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 694. Found: 694.

Part B. Methyl N² -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate

MS(ESI) Calc. for (M+1)⁺ : 494. Found: 494.

EXAMPLE 440

Methyl N² -[2-{2-(4-amidinophenyl)-1,3,4-thiodiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

Part A. Methyl N² -[2-{2-(4-cyanophenyl)-1,3,4-thiodiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-(S)-diaminopropionate

The same coupling reaction conditions as Part J of Example 1 were adopted to prepare this compound from 2-{2-(4-cyanophenyl)-1,3,4-thiodiazol-5-ylthio}acetic acid and Methyl N³ -n-butyloxycarbonyl-(S)-2,3-diaminopropionate HCO2H salt. ¹ H NMR(300 MHz, CDCl₃) δ0.92(t, J=8, 3H), 1.32(m, 2H), 1.56(m, 2H), 3.60(m, 2H), 3.80(s, 3H), 4.04(t, J=8, 2H), 4.58(m, 1H), 5.40(t, J=6, 1H), 7.50(d, J=6, 1H), 7.94(d, J=8, 2H), 8.10(d, J=8, 2H); MS(NH₃ -CI) Calc. for (M+1)⁺ : 478. Found: 478.

Part B. Methyl N² -[2-{2-(4-amidinophenyl)-1,3,4-thiodiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt

A similar procedure to Part C of Example 258 was adopted to prepare this material. ¹ H NMR(300 MHz, CDCl₃) δ0.88(t, J=8, 3H), 1.30(m, 2H), 1.50(m, 2H), 3.50(m, 2H), 3.88(s, 3H), 4.10(t, J=8, 2H), 4.50(m, 1H), 7.98(d, J=8, 2H), 8.12(d, J=8, 2H); MS(ESI) Calc. for (M+1)⁺ : 495. Found: 495(free base).

The previous working examples are shown in Table 1 and additional examples of compounds of the invention are shown in Table 1 and table 2 which can be prepared by the schemes and procedure discussed above or variations thereof obvious to those skilled in the art using appropriate starting materials.

                                      TABLE 1                                      __________________________________________________________________________      ##STR18##                                                                                                          Y                                         Ex No.                                                                             R.sup.1 Ar                                                                               m A W   R.sup.5                                                                           R           [(M + 1).sup.+ ]                                                                    MS                                   __________________________________________________________________________     1   4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OMe  463                                  2   4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH   449                                  4   4-amidinophenyl                                                                          0 S (CH.sub.2).sub.2                                                                   H  n-butyloxycarbonyl                                                                         OH                                        5   4-amidinophenyl                                                                          0 S (CH.sub.2).sub.3                                                                   H  n-butyloxycarbonyl                                                                         OH                                        6   4-amidinophenyl                                                                          1 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        7   4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Me n-butyloxycarbonyl                                                                         OH                                        8   4-amidinophenyl                                                                          2 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        9   4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  H           OH                                        10  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        11  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  t-butyloxycarbonyl                                                                         OH                                        12  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  ethyloxycarbonyl                                                                           OH                                        13  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  methyloxycarbonyl                                                                          OH                                        14  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-pentyloxycarbonyl                                                                        OH                                        15  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-hexyloxycarbonyl                                                                         OH                                        16  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  phenylethylcarbonyl                                   17  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2,2-dimethylpropylcarbonyl                                                                 OH                                        18  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-pentylcarbonyl                                                                           OH                                        19  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-butylcarbonyl                                                                            OH                                        20  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  propionyl   OH                                        21  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  acetyl      OH                                        22  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  methylsulfonyl                                                                             OH                                        23  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  ethylsulfonyl                                                                              OH                                        24  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  n-butylsulfonyl                                                                            OH                                        25  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  517                                  26  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH   503                                  27  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                        28  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                        29  4-amidinophenyl                                                                          0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        30  4-amidinophenyl                                                                          1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        31  4-amidinophenyl                                                                          2 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        32  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        33  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  4-methylsulfonyl                                                                           OH                                        34  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                        35  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                        36  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3-pyridylcarbonyl                                                                          OH                                        37  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  4-pyridylcarbonyl                                                                          OH                                        38  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2-pyridylmethylcarbonyl                                                                    OH                                        39  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3-pyridylmethylcarbonyl                                                                    OH                                        40  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  4-pyridylmethylcarbonyl                                                                    OH                                        41  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2-pyridylmethoxycarbonyl                                                                   OH                                        42  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3-pyridylmethoxycarbonyl                                                                   OH                                        43  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  4-pyridylmethoxycarbonyl                                                                   OH                                        44  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  531                                      phenyl                                                                     45  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                            phenyl                                                                     46  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  n-hexyloxycarbonyl                                                                         OH                                            phenyl                                                                     47  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  styrylsulfonyl                                                                             OH                                            phenyl                                                                     48  4-(N-methylamidino)                                                                      1 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                            phenyl                                                                     49  4-(N-methylamidino)                                                                      2 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                            phenyl                                                                     50  4-(N-methylamidino)                                                                      1 S CH.sub.2                                                                           H  3-methylphenylsufonyl                                                                      OH                                            phenyl                                                                     51  4-(N-methylamidino)                                                                      0 S (CH.sub.2).sub.2                                                                   H  2-methylphenylsufonyl                                                                      OH                                            phenyl                                                                     52  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     53  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           Me n-butyloxycarbonyl                                                                         OH                                            phenyl                                                                     54  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     55  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  phenylsufonyl                                                                              OH                                            phenyl                                                                     56  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  benzylsufonyl                                                                              OH                                            phenyl                                                                     57  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     58  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  3-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     59  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  4-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     60  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  2-pyridylmethylcarbonyl                                                                    OH                                            phenyl                                                                     61  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  3-pyridylmethylcarbonyl                                                                    OH                                            phenyl                                                                     62  4-(N-methylamidino)                                                                      0 S CH.sub.2                                                                           H  4-pyridylmethylcarbonyl                                                                    OH                                            phenyl                                                                     63  4-(N-methylamidino)-                                                                     0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH   517                                      phenyl                                                                     64  4-(N-n-butylamidino)-                                                                    0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  573                                      phenyl                                                                     65  4-(N-n-butylamidino)-                                                                    0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH   559                                      phenyl                                                                     67  4-(N-n-butylamidino)-                                                                    1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     68  4-(N-n-butylamidino)-                                                                    2 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     69  4-(N-n-butylamidino)-                                                                    0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     70  4-(N-n-butylamidino)-                                                                      S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     71  4-(N-n-butylamidino)-                                                                    1 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     72  4-(N-ethylamidino)-                                                                      1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     73  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     74  4-(N-ethylamidino)-                                                                      2 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     75  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     76  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     77  4-(N-ethylamidino)-                                                                      0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     78  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     79  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     80  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                            phenyl                                                                     81  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  2-pyridylsulfonyl                                                                          OH                                            phenyl                                                                     82  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  3-pyridylsulfonyl                                                                          OH                                            phenyl                                                                     83  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  4-pyridylsulfonyl                                                                          OH                                            phenyl                                                                     84  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     85  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  3-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     87  4-(N-ethylamidino)-                                                                      0 S CH.sub.2                                                                           H  4-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     88  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OMe  517                                  89  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH   503                                  90  4-amidinophenyl                                                                          1 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        91  4-amidinophenyl                                                                          2 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        92  4-amidinophenyl                                                                          0 S (CH.sub.2).sub.2                                                                   H  2-methylphenylsulfonyl                                                                     OH                                        93  4-amidinophenyl                                                                          0 S (CH.sub.2).sub.3                                                                   H  2-methylphenylsulfonyl                                                                     OH                                        94  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Me 2-methylphenylsulfonyl                                                                     OH                                        95  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Et 2-methylphenylsulfonyl                                                                     OH                                        96  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-4-yl-                                                                 OMe  522                                                           sulfonyl                                              97  4-amidinophenyl                                                                          0 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-4-yl-                                                                 OH   508                                                           sulfonyl                                              98  4-amidinophenyl                                                                          1 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              99  4-amidinophenyl                                                                          2 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              100 4-amidinophenyl                                                                          0 S (CH.sub.2).sub.2                                                                   H  3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              101 4-amidinophenyl                                                                          0 S (CH.sub.2).sub.3                                                                   H  3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              102 4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Me 3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              103 4-amidinophenyl                                                                          0 S CH.sub.2                                                                           Et 3,5-dimethylisoxazol-4-yl-                                                                 OH                                                                 sulfonyl                                              104 4-piperidinyl                                                                            0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  482                                  105 4-piperidinyl                                                                            0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        106 4-piperidinyl                                                                            1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        107 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        108 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        109 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        110 4-piperidinyl                                                                            2 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                        111 4-piperidinyl                                                                            2 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                        112 4-piperidinyl                                                                            1 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        113 4-piperidinyl                                                                            2 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        114 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        115 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          116 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                        117 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  2-pyridylsulfonyl                                                                          OH                                        118 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  3-pyridylsulfonyl                                                                          OH                                        119 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  4-pyridylsulfonyl                                                                          OH                                        120 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  2-pyridylmethylsulfonyl                                                                    OH                                        121 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  3-pyridylmethylsulfonyl                                                                    OH                                        122 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  4-pyridylmethylsulfonyl                                                                    OH                                        123 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                        124 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  3-pyridylcarbonyl                                                                          OH                                        125 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  4-pyridylcarbonyl                                                                          OH                                        126 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  2-pyridylsulfonyl                                                                          OH                                        127 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        128 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        129 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  ethyloxycarbonyl                                                                           OH                                        130 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  n-hexyloxycarbonyl                                                                         OH                                        131 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  methyloxycarbonyl                                                                          OH                                        132 4-piperidinyl                                                                            2 S CH.sub.2                                                                           H  n-propylloxycarbonyl                                                                       OH                                        133 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  3-methylphenylsulfonyl                                                                     OMe  510                                  134 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  3-methylphenylsulfonyl                                                                     OH   496                                  135 4-piperidinyl                                                                            1 S (CH.sub.2).sub.3                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        136 4-piperidinyl                                                                            2 S (CH.sub.2).sub.3                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        137 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   Et 3-methylphenylsulfonyl                                                                     OH                                        138 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   Me 3-methylphenylsulfonyl                                                                     OH                                        139 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  2-methylphenylsulfonyl                                                                     OH                                        140 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  4-methylphenylsulfonyl                                                                     OH                                        141 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  phenylsulfonyl                                                                             OH                                        142 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  benzyloxycarbonyl                                                                          OH                                        143 4-piperidinyl                                                                            0 S (CH.sub.2).sub.3                                                                   H  n-butyloxycarbonyl                                                                         OH                                        144 4-[N,N'-di(trifluoro-                                                                    0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  681                                      ethyl)amindino]phenyl                                                      145 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  532                                  146 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH   518                                  147 4-guanidinophenyl                                                                        1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        148 4-guanidinophenyl                                                                        0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        149 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                        150 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                        151 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        152 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        153 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        154 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          155 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        156 4-guanidinophenyl                                                                        0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        157 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  533                                      dino)phenyl                                                                158 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                159 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                160 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                161 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                162 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                163 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                            dino)phenyl                                                                164 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                            dino)phenyl                                                                165 4-(N-hydroxylami-                                                                        1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                166 4-(N-hydroxylami-                                                                        0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                            dino)phenyl                                                                167 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  3,5-dimthylisoxazol-                                                                       OH                                            dino)phenyl          4-ylsulfonyl                                          168 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                            dino)phenyl                                                                169 4-(N-hydroxylami-                                                                        0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                            dino)phenyl                                                                170 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OMe  518                                  171 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH   504                                  172 4-amidophenyl                                                                            1 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        173 4-amidophenyl                                                                            2 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        174 4-amidophenyl                                                                            0 S (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        175 4-amidophenyl                                                                            0 S CH.sub.2                                                                           Me 3-methylphenylsulfonyl                                                                     OH                                        176 4-amidophenyl                                                                            0 S CH.sub.2                                                                           Et 3-methylphenylsulfonyl                                                                     OH                                        177 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        178 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        179 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        180 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          181 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        182 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        183 4-amidophenyl                                                                            0 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                        184 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     185 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                            phenyl                                                                     186 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                            phenyl                                                                     187 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                            phenyl                                                                     188 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                            phenyl                                                                     189 4-(N-methylamido)-                                                                       0 S CH.sub.2                                                                           H  2-pyridylcarbonyl                                                                          OH                                            phenyl                                                                     190 4-(N,N-dimethyl-                                                                         0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                            amido)phenyl                                                               191 4-(N-methyl-N-ethyl)-                                                                    0 S CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                            amidophenyl                                                                192 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OMe  495                                  193 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH   481                                  194 4-amidinophenyl                                                                          0 S S(CH.sub.2).sub.2                                                                  H  n-butyloxycarbonyl                                                                         OH                                        195 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          Me n-butyloxycarbonyl                                                                         OH                                        196 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          Et n-butyloxycarbonyl                                                                         OH                                        197 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  benzylcarbonyl                                                                             OH                                        198 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  methyloxycarbonyl                                                                          OH                                        199 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  ethyloxycarbonyl                                                                           OH                                        200 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        201 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        202 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        203 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        204 4-amidinophenyl                                                                          0 S SCH.sub.2                                                                          H  benzylsulfonyl                                                                             OH                                        205 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        206 4-pyperidinyl                                                                            1 S SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        207 4-pyperidinyl                                                                            2 S SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        208 4-pyperidinyl                                                                            2 S SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        209 4-pyperidinyl                                                                            2 S SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        210 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        211 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        212 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  benzylsulfonyl                                                                             OH                                        213 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  n-butylsulfonyl                                                                            OH                                        214 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        215 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  benzyloxycarbonyl                                                                          OH                                        216 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  n-butylcarbonyl                                                                            OH                                        217 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  methlcarbonyl                                                                              OH                                        218 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          H  ethylcarbonyl                                                                              OH                                        219 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          Me n-butylcarbonyl                                                                            OH                                        220 4-pyperidinyl                                                                            0 S SCH.sub.2                                                                          Et n-butylcarbonyl                                                                            OH                                        221 4-pyperidinyl                                                                            0 S S(CH.sub.2).sub.2                                                                  H  n-butylcarbonyl                                                                            OH                                        222 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OMe  452                                  223 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        224 4-aminophenyl                                                                            0 S SCH.sub.2                                                                          Me n-butyloxycarbonyl                                                                         OH                                        225 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          Et n-butyloxycarbonyl                                                                         OH                                        226 4-aminophenyl                                                                            1 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        227 4-aminophenyl                                                                            2 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        228 4-aminophenyl                                                                            0 O S(CH.sub.2).sub.2                                                                  H  n-butyloxycarbonyl                                                                         OH                                        229 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  benzylloxycarbonyl                                                                         OH                                        230 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  methyloxycarbonyl                                                                          OH                                        231 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        232 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  3-methylsulfonyl                                                                           OH                                        233 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  2-methylsulfonyl                                                                           OH                                        234 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  4-methylsulfonyl                                                                           OH                                        235 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  benzylsulfonyl                                                                             OH                                        236 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  n-butylsulfonyl                                                                            OH                                        237 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          238 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  2-pyridylcarbonyl                                                                          OH                                        239 4-aminophenyl                                                                            0 O SCH.sub.2                                                                          H  3-pyridylsulfonyl                                                                          OH                                        240 4-(dimethyl)amino-                                                                       0 O SCH.sub.2                                                                          H  3-methylsulfonyl                                                                           OH                                            phenyl                                                                     241 4-methylamino-                                                                           0 O SCH.sub.2                                                                          H  3-methylsulfonyl                                                                           OH                                            phenyl                                                                     242 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OMe  494                                  243 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        244 4-guanidinophenyl                                                                        1 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        245 4-guanidinophenyl                                                                        2 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        246 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        247 4-guanidinophenyl                                                                        0 O S(CH.sub.2).sub.2                                                                  H  n-butyloxycarbonyl                                                                         OH                                        248 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          Me n-butyloxycarbonyl                                                                         OH                                        249 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          Et n-butyloxycarbonyl                                                                         OH                                        250 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  benzylloxycarbonyl                                                                         OH                                        251 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  ethyloxycarbonyl                                                                           OH                                        252 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  n-butylsulfonyl                                                                            OH                                        253 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        254 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        255 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        256 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        257 4-guanidinophenyl                                                                        0 O SCH.sub.2                                                                          H  benzylsulfonyl                                                                             OH                                        258 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OMe  479                                  259 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        260 4-amidinophenyl                                                                          1 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        261 4-amidinophenyl                                                                          2 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        262 4-amidinophenyl                                                                          0 O S(CH.sub.2).sub.2                                                                  H  n-butyloxycarbonyl                                                                         OH                                        263 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          Me n-butyloxycarbonyl                                                                         OH                                        264 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          Et n-butyloxycarbonyl                                                                         OH                                        265 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  benzyloxycarbonyl                                                                          OH                                        267 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  methyloxycarbonyl                                                                          OH                                        268 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  ethyloxycarbonyl                                                                           OH                                        269 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  n-butylsulfonyl                                                                            OH                                        270 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  benzylsulfonyl                                                                             OH                                        271 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        272 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        273 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        274 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        275 4-amidinophenyl                                                                          0 O SCH.sub.2                                                                          H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          276 4-pyperidinyl                                                                            0 O SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        277 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        278 4-pyperidinyl                                                                            2 O SCH.sub.2                                                                          H  2-methylphenylsulfonyl                                                                     OH                                        279 4-pyperidinyl                                                                            0 O S(CH.sub.2).sub.2                                                                  H  2-methylphenylsulfonyl                                                                     OH                                        280 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          Me 2-methylphenylsulfonyl                                                                     OH                                        281 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          Et 2-methylphenylsulfonyl                                                                     OH                                        281 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  3-methylphenylsulfonyl                                                                     OH                                        282 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  4-methylphenylsulfonyl                                                                     OH                                        283 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  phenylsulfonyl                                                                             OH                                        284 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  n-butylsulfonyl                                                                            OH                                        285 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          286 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  benzyloxycarbonyl                                                                          OH                                        287 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  n-butyloxycarbonyl                                                                         OH                                        288 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  methyloxycarbonyl                                                                          OH                                        289 4-pyperidinyl                                                                            1 O SCH.sub.2                                                                          H  ethylyloxycarbonyl                                                                         OH                                        290 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OMe  420                                  291 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        292 4-aminophenyl                                                                            1 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        293 4-aminophenyl                                                                            2 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        294 4-aminophenyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  n-butyloxycarbonyl                                                                         OH                                        295 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        296 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  methyloxycarbonyl                                                                          OH                                        297 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  ethyloxycarbonyl                                                                           OH                                        298 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        299 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        300 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        301 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        302 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          303 4-aminophenyl                                                                            0 O CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                        304 4-pyperidinyl                                                                            0 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        305 4-pyperidinyl                                                                            1 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        306 4-pyperidinyl                                                                            2 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        307 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  2-methylphenylsulfonyl                                                                     OH                                        308 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  3-methylphenylsulfonyl                                                                     OH                                        309 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  4-methylphenylsulfonyl                                                                     OH                                        310 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  phenylsulfonyl                                                                             OH                                        312 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  benzyloxysulfonyl                                                                          OH                                        313 4-pyperidinyl                                                                            0 O (CH.sub.2).sub.2                                                                   H  n-butylsulfonyl                                                                            OH                                        314 4-pyperidinyl                                                                            2 O CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        315 4-pyperidinyl                                                                            2 O CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        316 4-pyperidinyl                                                                            2 O CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        317 4-pyperidinyl                                                                            2 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        318 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OMe  447                                  319 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        320 4-amidinophenyl                                                                          1 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        321 4-amidinophenyl                                                                          2 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        322 4-amidinophenyl                                                                          0 O (CH.sub.2).sub.2                                                                   H  n-butyloxycarbonyl                                                                         OH                                        323 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           Me n-butyloxycarbonyl                                                                         OH                                        324 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           Et n-butyloxycarbonyl                                                                         OH                                        325 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        326 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        327 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        328 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        329 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                        330 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  n-butylsulfonyl                                                                            OH                                        331 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  ethylsulfonyl                                                                              OH                                        332 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        333 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  methyloxycarbonyl                                                                          OH                                        334 4-amidinophenyl                                                                          0 O CH.sub.2                                                                           H  ethyloxycarbonyl                                                                           OH                                        335 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OMe  462                                  336 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        337 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           Me n-butyloxycarbonyl                                                                         OH                                        338 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           Et n-butyloxycarbonyl                                                                         OH                                        339 4-guanidinophenyl                                                                        1 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        340 4-guanidinophenyl                                                                        2 O CH.sub.2                                                                           H  n-butyloxycarbonyl                                                                         OH                                        341 4-guanidinophenyl                                                                        0 O (CH.sub.2).sub.2                                                                   H  n-butyloxycarbonyl                                                                         OH                                        342 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  benzyloxycarbonyl                                                                          OH                                        343 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  methyloxycarbonyl                                                                          OH                                        344 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  ethyloxycarbonyl                                                                           OH                                        345 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  n-butylsulfonyl                                                                            OH                                        346 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  benzylsulfonyl                                                                             OH                                        347 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  phenylsulfonyl                                                                             OH                                        348 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  2-methylphenylsulfonyl                                                                     OH                                        349 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  3-methylphenylsulfonyl                                                                     OH                                        350 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  4-methylphenylsulfonyl                                                                     OH                                        351 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           Me 2-methylphenylsulfonyl                                                                     OH                                        352 4-guanidinophenyl                                                                        0 O CH.sub.2                                                                           H  3,5-dimethylisoxazol-                                                                      OH                                                                 4-ylsulfonyl                                          __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR19##                                                                                                        Y                                           Ex No.                                                                             R.sup.1 Ar m A W   R.sup.5                                                                          X         [(M + 1).sup.+ ]                                                                    MS                                     __________________________________________________________________________     353 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H CH.sub.2  OMe                                             323                                                                        354 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H CH.sub.2  OH                                          355 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          H CH.sub.2  OH                                          356 4-aminophenyl                                                                             2 O SCH.sub.2                                                                          H CH.sub.2  OH                                          357 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          Me                                                                               CH.sub.2  OH                                          358 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                          359 4-aminophenyl                                                                             0 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          360 4-aminophenyl                                                                             0 O S(CH.sub.2).sub.3                                                                  H CH.sub.2  OH                                          361 4-aminophenyl                                                                             1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          363 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                          363 4-(N-methylamino)-                                                                        1 O SCH.sub.2                                                                          H CH.sub.2  OH                                              phenyl                                                                     364 4-(N-methylamino)-                                                                        1 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                              phenyl                                                                     365 4-(N-methylamino)-                                                                        0 O SCH.sub.2                                                                          H CH.sub.2  OH                                              phenyl                                                                     366 4-(N,N-dimethylamino)-                                                                    1 O SCH.sub.2                                                                          H CH.sub.2  OH                                              phenyl                                                                     367 4-(N,N-dimethylamino)-                                                                    0 O SCH.sub.2                                                                          H CH.sub.2  OH                                              phenyl                                                                     368 4-(N,N-dimethylamino)-                                                                    1 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                              phenyl                                                                     369 4-(N,N-dimethylamino)-                                                                    1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                              phenyl                                                                     370 4-amino-2-fluorophenyl                                                                    0 O SCH.sub.2                                                                          H CH.sub.2  OH                                          371 4-amino-2-fluorophenyl                                                                    1 O SCH.sub.2                                                                          H CH.sub.2  OH                                          372 4-amino-2-fluorophenyl                                                                    0 O SCH.sub.2                                                                          Me                                                                               CH.sub.2  OH                                          373 4-amino-2-fluorophenyl                                                                    0 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                          374 4-amino-2-fluorophenyl                                                                    0 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          375 4-amino-2-fluorophenyl                                                                    1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          376 4-amino-3-fluorophenyl                                                                    0 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          377 4-amino-3-fluorophenyl                                                                    1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          378 4-pyperidinyl                                                                             0 O SCH.sub.2                                                                          H CH.sub.2  OH                                          379 4-pyperidinyl                                                                             1 O SCH.sub.2                                                                          H CH.sub.2  OH                                          380 4-pyperidinyl                                                                             2 O SCH.sub.2                                                                          H CH.sub.2  OH                                          381 4-pyperidinyl                                                                             3 O SCH.sub.2                                                                          H CH.sub.2  OH                                          382 4-pyperidinyl                                                                             0 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          383 4-pyperidinyl                                                                             0 O S(CH.sub.2).sub.3                                                                  H CH.sub.2  OH                                          384 4-pyperidinyl                                                                             1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          385 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H CH.sub.2  OMe                                             365                                                                        386 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H CH.sub.2  OH                                          387 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          H CH.sub.2  OH                                          388 4-guanidinophenyl                                                                         1 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          389 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          Et                                                                               CH.sub.2  OH                                          390 4-guanidinophenyl                                                                         2 O SCH.sub.2                                                                          H CH.sub.2  OH                                          391 4-guanidinophenyl                                                                         0 O S(CH.sub.2).sub.2                                                                  H CH.sub.2  OH                                          392 4-guanidinophenyl 455                                                                     0 O SCH.sub.2                                                                          H                                                                                 ##STR20##                                                                               OMe                                         393 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR21##                                                                               OH                                          394 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          H                                                                                 ##STR22##                                                                               OH                                          395 4-guanidinophenyl                                                                         2 O SCH.sub.2                                                                          H                                                                                 ##STR23##                                                                               OH                                          396 4-guanidinophenyl                                                                         0 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR24##                                                                               OH                                          397 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          Et                                                                                ##STR25##                                                                               OH                                          398 4-guanidinophenyl                                                                         1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR26##                                                                               OH                                          399 4-amidinophenyl 454                                                                       0 O SCH.sub.2                                                                          H                                                                                 ##STR27##                                                                               OEt                                         400 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR28##                                                                               OH                                          401 4-amidinophenyl                                                                           1 O SCH.sub.2                                                                          H                                                                                 ##STR29##                                                                               OH                                          402 4-amidinophenyl                                                                           2 O SCH.sub.2                                                                          H                                                                                 ##STR30##                                                                               OH                                          403 4-amidinophenyl                                                                           0 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR31##                                                                               OH                                          404 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR32##                                                                               OMe  452                                    405 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR33##                                                                               OH                                          406 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          H                                                                                 ##STR34##                                                                               OH                                          407 4-aminophenyl                                                                             2 O SCH.sub.2                                                                          H                                                                                 ##STR35##                                                                               OH                                          408 4-aminophenyl                                                                             1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR36##                                                                               OH                                          409 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          Et                                                                                ##STR37##                                                                               OH                                          410 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR38##                                                                               OH                                          411 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          H                                                                                 ##STR39##                                                                               OH                                          412 4-aminophenyl                                                                             2 O SCH.sub.2                                                                          H                                                                                 ##STR40##                                                                               OH                                          413 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          Me                                                                                ##STR41##                                                                               OH                                          414 4-aminophenyl                                                                             1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR42##                                                                               OH                                          415 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR43##                                                                               OH                                          416 4-aminophenyl                                                                             1 O SCH.sub.2                                                                          H                                                                                 ##STR44##                                                                               OH                                          417 4-aminophenyl                                                                             1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR45##                                                                               OH                                          418 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          Et                                                                                ##STR46##                                                                               OH                                          419 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR47##                                                                               OH                                          420 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR48##                                                                               OH                                          421 4-aminophenyl                                                                             0 O SCH.sub.2                                                                          H                                                                                 ##STR49##                                                                               OH                                          422 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR50##                                                                               OMe  494                                    423 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR51##                                                                               OH                                          424 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          H                                                                                 ##STR52##                                                                               OH                                          425 4-guanidinophenyl                                                                         2 O SCH.sub.2                                                                          H                                                                                 ##STR53##                                                                               OH                                          426 4-guanidinophenyl                                                                         1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR54##                                                                               OH                                          427 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          Et                                                                                ##STR55##                                                                               OH                                          428 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR56##                                                                               OH                                          429 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          H                                                                                 ##STR57##                                                                               OH                                          430 4-guanidinophenyl                                                                         2 O SCH.sub.2                                                                          H                                                                                 ##STR58##                                                                               OH                                          431 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          Me                                                                                ##STR59##                                                                               OH                                          432 4-guanidinophenyl                                                                         1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR60##                                                                               OH                                          433 4-aguanidinophenyl                                                                        0 O SCH.sub.2                                                                          H                                                                                 ##STR61##                                                                               OH                                          434 4-guanidinophenyl                                                                         1 O SCH.sub.2                                                                          H                                                                                 ##STR62##                                                                               OH                                          435 4-guanidinophenyl                                                                         1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR63##                                                                               OH                                          436 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          Et                                                                                ##STR64##                                                                               OH                                          437 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR65##                                                                               OH                                          438 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR66##                                                                               OH                                          439 4-guanidinophenyl                                                                         0 O SCH.sub.2                                                                          H                                                                                 ##STR67##                                                                               OH                                          440 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR68##                                                                               OMe  495                                    441 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR69##                                                                               OH                                          442 4-amidinophenyl                                                                           1 O SCH.sub.2                                                                          H                                                                                 ##STR70##                                                                               OH                                          443 4-amidinophenyl                                                                           2 O SCH.sub.2                                                                          H                                                                                 ##STR71##                                                                               OH                                          444 4-amidinophenyl                                                                           1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR72##                                                                               OH                                          445 4-amidinophenyl                                                                           1 O SCH.sub.2                                                                          Et                                                                                ##STR73##                                                                               OH                                          446 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR74##                                                                               OH                                          447 4-amidinophenyl                                                                           1 O SCH.sub.2                                                                          H                                                                                 ##STR75##                                                                               OH                                          448 4-amidinophenyl                                                                           2 O SCH.sub.2                                                                          H                                                                                 ##STR76##                                                                               OH                                          449 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          Me                                                                                ##STR77##                                                                               OH                                          450 4-amidinophenyl                                                                           1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR78##                                                                               OH                                          451 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR79##                                                                               OH                                          452 4-amidinophenyl                                                                           1 O SCH.sub.2                                                                          H                                                                                 ##STR80##                                                                               OH                                          453 4-amidinophenyl                                                                           1 O S(CH.sub.2).sub.2                                                                  H                                                                                 ##STR81##                                                                               OH                                          454 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          Et                                                                                ##STR82##                                                                               OH                                          455 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR83##                                                                               OH                                          456 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR84##                                                                               OH                                          457 4-amidinophenyl                                                                           0 O SCH.sub.2                                                                          H                                                                                 ##STR85##                                                                               OH                                          __________________________________________________________________________

Utility

The compounds of this invention possess antiplatelet efficacy, as evidenced by their activity in standard platelet aggregation assays or platelet fibrinogen binding assays, as described below. A compound is considered to be active in these assays if it has an IC₅₀ value of less than about 1 mM. Platelet aggregation and fibrinogen binding assays which may be used to demonstrate the antiplatelet activity of the compounds of the invention are described below.

Platelet Aggregation Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin-free for at least two weeks prior to blood collection. Blood was collected into 10 mL citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150× g at room temperature, and platelet-rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500× g at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a aggregometer (PAP-4 Platelet Aggregation Profiler), using PPP as the blank (100% transmittance). 200 μL of PRP was added to each micro test tube, and transmittance was set to 0%. 20 μL of various agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added to each tube, and the aggregation profiles were plotted (% transmittance versus time). The results are expressed as % inhibition of agonist-induced platelet aggregation. For the IC₅₀ evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

Ester prodrugs were preincubated (10⁻³ M F.C.) with 100 IU/mL Porcine liver esterase (Sigma Chemical Co., St. Louis, Mo., #E-3128) for 2 hours at 37° C. Aliquots are then diluted in 0.1M Tris, p H 7.4, to the desired concentrations. Aliquots of 20 μl of the esterase pretreated prodrugs are added to 200 μl of human platelet rich plasma. Samples were placed in platelet profiler (aggregometer) for 8 minutes at 37° C., followed by the addition of 100 μM Adenosine Diphosphate, (Sigma Chemical Co., St. Louis, Mo., #A-6521), to induce platelet aggregation. Platelet aggregation was allowed to proceed for 5 minutes. Percent inhibition is calculated using percent aggregation in the presence of the test compound divided by percent aggregation of control, times 100. This value is subtracted from 100, yielding percent inhibition. Calculation of IC₅₀ is performed on a Texas Instruments TI59 with an IC₅₀ program.

Purified GPIIb/IIIa-Fibrinogen Binding ELISA

The following reagents are used in the GPIIb/IIIa-fibrinogen binding ELISA:

purified GPIIb/IIIa (148.8 μg/mL);

biotinylated fibrinogen (˜1 mg/mL or 3000 nM);

anti-biotin alkaline phosphatase conjugate (Sigma no. A7418);

flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590);

phosphatase substrate (Sigma 104) (40 mg capsules);

bovine serum albumin (BSA) (Sigma no. A3294);

Alkaline Phosphatase buffer -0.1M glycine-HCl, 1 mM MgCl₂.6H₂ O, 1 mM ZnCl₂, pH 10.4;

Binding buffer -20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl₂.2H₂ O, 0.02% NAN₃, pH 7.0;

Buffer A -50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl₂.2H₂ O, 0.02% NAN₃, pH 7.4;

Buffer A+3.5% BSA (Blocking buffer);

Buffer A+0.1% BSA (Dilution buffer);

2N NaOH.

The following method steps are used in the GPIIb/IIIa-fibrinogen binding ELISA:

Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 μL/well) overnight at 4° C. (Leave first column uncoated for non-specific binding). Cover and freeze plates at -70° C. until used. Thaw plate 1 hour at room temperature or overnight at 4° C. Discard coating solution and wash once with 200 μL Binding buffer per well. Block plate 2 hours at room temperature on shaker with 200 μL Buffer A+3.5% BSA (Blocking buffer) per well. Discard Blocking buffer and wash once with 200 μL Buffer A+0.1% BSA (Dilution buffer) per well. Pipet 11 μL of test compound (10× the concentration to be tested in Dilution buffer) into duplicate wells. Pipet 11 μL Dilution buffer into non-specific and total binding wells. Add 100 μL Biotinylated fibrinogen (1/133 in Dilution buffer, final concentration=20 nM) to each well. Incubate plates for 3 hours at room temperature on a plate shaker. Discard assay solution and wash twice with 300 μL Binding buffer per well. Add 100 μL Anti-biotin alkaline phosphatase conjugate (1/1500 in Dilution buffer) to each well. Incubate plates for 1 hour at room temperature on plate shaker. Discard conjugate and wash twice with 300 5l Binding buffer per well. Add 100 μL Phosphatase substrate (1.5 mg/mL in Alkaline phosphatase buffer) to each well. Incubate plate at room temperature on shaker until color develops. Stop color development by adding 25 μL 2N NaOH per well. Read plate at 405 nm. Blank against non-specific binding (NSB) well. % Inhibition is calculated as 100-(Test Compound Abs/Total Abs)×100.

Platelet-Fibrinogen Binding Assay: Binding of ¹²⁵ I-fibrinogen to platelets was performed as described by Bennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, with some modifications as described below. Human PRP (h-PRP) was applied to a Sepharose column for the purification of platelet fractions. Aliquots of platelets (5×10⁸ cells) along with 1 mM calcium chloride were added to removable 96 well plates prior to the activation of the human gel purified platelets (h-GPP). Activation of the human gel purified platelets was achieved using ADP, collagen, arachidonate, epinephrine, and/or thrombin in the presence of the ligand, ¹²⁵ I-fibrinogen. The ¹²⁵ I-fibrinogen bound to the activated platelets was separated from the free form by centrifugation and then counted on a gamma counter. For an IC₅₀ evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.

The compounds of Formula I of the present invention may also possess thrombolytic efficacy, that is, they are capable of lysing (breaking up) already formed platelet-rich fibrin blood clots, and thus are useful in treating a thrombus formation, as evidenced by their activity in the tests described below. Preferred compounds of the present invention for use in thrombolysis include those compounds having an IC₅₀ value (that is, the molar concentration of the compound capable of achieving 50% clot lysis) of less than about 1 μM, more preferably an IC₅₀ value of less than about 0.1 μM.

Thrombolytic Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin free for at least two weeks prior to blood collection, and placed into 10 ml citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 1500× g at room temperature, and platelet rich plasma (PRP) was removed. To the PRP was then added 1×10⁻³ M of the agonist ADP, epinephrine, collagen, arachidonate, serotonin or thrombin, or a mixture thereof, and the PRP incubated for 30 minutes. The PRP was centrifuged for 12 minutes at 2500× g at room temperature. The supernatant was then poured off, and the platelets remaining in the test tube were resuspended in platelet poor plasma (PPP), which served as a plasminogen source. The suspension was then assayed on a Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.), to determine the platelet count at the zero time point. After obtaining the zero time point, test compounds were added at various concentrations. Test samples were taken at various time points and the platelets were counted using the Coulter Counter. To determine the percent of lysis, the platelet count at a time point subsequent to the addition of the test compound was subtracted from the platelet count at the zero time point, and the resulting number divided by the platelet count at the zero time point. Multiplying this result by 100 yielded the percentage of clot lysis achieved by the test compound. For the IC₅₀ evaluation, the test compounds were added at various concentrations, and the percentage of lysis caused by the test compounds was calculated.

The compounds of Formula I of the present invention are also useful for administration in combination with anti-coagulant agents such as warfarin or heparin, or antiplatelet agents such as aspirin, piroxicam or ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or argatroban, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.

The compounds of Formula I of the present invention may also be useful as antagonists of other integrins such as for example, the α_(v) /β₃ or vitronectin receptor, α₄ /β₁ or α₅ /β₁ and as such may also have utility in the treatment and diagnosis of osteoporosis, cancer metastasis, diabetic retinopathy, rheumatoid arthritis, inflammation, and autoimmune disorders. The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.

Table A below sets forth the antiplatelet activity of representative compounds of the present invention. The indicated compounds were tested for their ability to inhibit platelet aggregation (using platelet rich plasma (PRP)). The IC₅₀ value (the concentration of antagonist which inhibits platelet aggregation by 50% relative to a control lacking the antagonist) is shown. In Table A the IC₅₀ values are expressed as: +++=IC₅₀ of <10 μM; ++=IC₅₀ of 10-50M; +=IC₅₀ of 50-100 μM (μM=micromolar).

                  TABLE A                                                          ______________________________________                                                    Platelet     Platelet                                                          Aggregation Assay                                                                           Aggregation Assay                                      Example    IC.sub.50 (without                                                                          IC.sub.50 (with                                        Number     esterase)    esterase)                                              ______________________________________                                          1                      +++                                                     2         +++                                                                  25                     +++                                                     26        +++                                                                  44                     +++                                                     63        +++                                                                  64                     +++                                                     65        +++                                                                  88                     +++                                                     89        +++                                                                  96                     +++                                                     97        +++                                                                 133                     +++                                                    134        +++                                                                 145                     +++                                                    146        +++                                                                 170                     +                                                      171        +++                                                                 192                     +++                                                    193        +++                                                                 242                     ++                                                     258                     +++                                                    318                     +                                                      335                     +++                                                    392                     ++                                                     399                     ++                                                     440                     +++                                                    ______________________________________                                    

Dosage and Formulation

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. Finally, the compounds of the invention may also be administered intranasally.

The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents, such as a second antiplatelet agent such as aspirin or ticlopidine which are agonist-specific. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1-20 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 1-20 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 1-20 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5 mL contain 1-20 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered in combination with a second therapeutic agent selected from: an anti-coagulant agent such as warfarin or heparin; an anti-platelet agent such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as a boropeptide thrombin inhibitor, or hirudin; or a thrombolytic agent such as plasminogen activators, such as tissue plasminogen activator, anistreplase, urokinase or streptokinase. The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.

The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent). When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic agent occurs less than about one hour apart.

A preferable route of administration of the compound of Formula I is oral. Although it is preferable that the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

Although the proper dosage of the compound of Formula I when administered in combination with the second therapeutic agent will be readily ascertainable by a medical practitioner skilled in the art, once armed with the present disclosure, by way of general guidance, where the compounds of this invention are combined with anti-coagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the anti-coagulant, per kilogram of patient body weight. For a tablet dosage form, the novel compounds of this invention generally may be present in an amount of about 1 to 10 milligrams per dosage unit, and the anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with a second anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the additional anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Further, by way of general guidance, where the compounds of Formula I are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, for example, in the inhibition of platelet aggregation, the treatment of blood clots, and/or the treatment of thromboembolic disorders, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized. 

What is claimed is:
 1. A compound of the formula ##STR86## or a pharmaceutically acceptable salt thereof wherein: R¹ is selected from R² HN--, R² HN(R² N═)C--, R² HN(CH₂)_(q) Z--, R² HN(R² N═)C(CH₂)_(q) Z--, R² HN(R² N═)CN(R²)--, R² HNC(O)--, R² (R⁵ O)N(R² N═)C--, or R² HN(R⁵ ON═)C--;alternatively, R¹ is H when Ar is -(piperidinyl)-; q is 1-3; Z is selected from a bond (i.e. is absent), O, S, or S(═O), S(═O)₂ ; R² is selected from H, aryl (C₁ -C₁₀ alkoxy)carbonyl, or C₁ -C₁₀ alkoxycarbonyl, C₁ -C₄ alkyl, C₃ -C₆ alkenyl; R⁵ is selected from H or C₁ -C₁₀ alkyl substituted with 0-1 R^(4b) ; R^(4b) is selected from C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₇ cycloalkyl, C₇ -C₁₄ bicycloalkyl, hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, nitro, C₁ -C₆ alkylcarbonyl, C₆ -C₁₀ aryl, --N(R¹²)R¹³ ; halo, CF₃, CN, C₁ -C₆ alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl; Ar is selected from:-(piperidinyl)- substituted with 0-2 R^(6a), -(phenyl)- substituted with 0-2 R^(6a), or -(pyridyl)- substituted with 0-2 R^(6a) ; R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ; A is selected from O or S; W is selected from --(CH₂)_(n) -- or --S(CH₂)_(n-1) --; X is selected from --C(CH₂ --Ph)H--, --CH₂ --, --CH₂ C(NHR¹²)H-- or --C(CH₂ NHR¹²)H--; Y is selected from hydroxy, C₁ to C₁₀ alkyloxy, C₃ to C₁₁ cycloalkyloxy, C₆ to C₁₀ aryloxy, C₇ to C₁₁ aralkyloxy, C₃ to C₁₀ alkylcarbonyloxyalkyloxy, C₃ to C₁₀ alkoxycarbonyloxyalkyloxy, C₂ to C₁₀ alkoxycarbonylalkyloxy, C₅ to C₁₀ cycloalkylcarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonyloxyalkyloxy, C₅ to C₁₀ cycloalkoxycarbonylalkyloxy, C₇ to C₁₁ aryloxycarbonylalkyloxy, C₈ to C₁₂ aryloxycarbonyloxyalkyloxy, C₈ to C₁₂ arylcarbonyloxyalkyloxy, C₅ to C₁₀ alkoxyalkylcarbonyloxyalkyloxy, C₅ to C₁₀ (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C₁₀ to C₁₄ (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R²)HN--(C₁ -C₁₀ alkoxy)--; m is 0-2; n is 1-4; and R¹² and R¹³ are each independently selected from H; C₁ -C₁₀ alkyl; C₁ -C₁₀ alkoxycarbonyl; C₁ -C₁₀ alkylcarbonyl; C₁ -C₁₀ alkylsulfonyl; aryl, aryl(C₁ -C₁₀ alkyl)sulfonyl, and arylsulfonyl wherein said aryls and heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and heteroaryl(C₁ -C₄ alkyl)sulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroarylalkylcarbonyl wherein said heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ;provided that m and n are chosen such that the number of atoms connecting R¹ and y is in the range of 10-18.
 2. A compound of the formula ##STR87## wherein R¹ is selected from R² NHC(═NR²)-- or R² NHC(═NR²)NH--;R² is selected from H, C₁ -C₁₀ alkoxycarbonyl, or C₁ -C₄ alkyl; R⁵ is selected from H or C₁ -C₄ alkyl Ar is selected from -(phenyl)- substituted with 0-2 R^(6a), or -(piperidinyl)- substituted with 0-2 R^(6a) ; R^(6a) is selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, NO₂, or NR¹² R¹³ ; A is selected from O or S; W is selected from --(CH₂)_(n) -- or --S(CH₂)_(n-1) --; X is selected from --CH₂ C(NHR¹²)H-- or --C(CH₂ NHR¹²)H--; Y is selected from:hydroxy; C₁ to C₁₀ alkoxy; methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-; diethylaminoethoxy-; (5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-; (1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-; 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; m is 1 or 2; n is 1 or 2; R¹² is selected from H; C₁ -C₆ alkyl; C₁ -C₄ alkoxycarbonyl; C₁ -C₆ alkylcarbonyl; C₁ -C₆ alkylsulfonyl; aryl, aryl(C₁ -C₄ alkyl)sulfonyl, and arylsulfonyl wherein said aryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and heteroaryl(C₁ -C₄ alkyl)sulfonyl, heteroarylsulfonyl, heteroarylcarbonyl or heteroarylmethylcarbonyl wherein said heteroaryls are substituted with 0-3 substituents selected from the group consisting of: C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo, CF₃, and NO₂ ; and R¹³ is H; ora pharmaceutically acceptable salt thereof.
 3. A compound of claim 2 selected from the group consisting of:Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-N-methylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-N-n-butylamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(2-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3,5-dimethylisoxazol-4-ylsulfonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[4-{2-(4-piperidinyl)-1,3,4-thiadiazol-5-yl}-butyryl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt Methyl N³ -[2-{2-(4-N,N'-di(trifluoroethyl)amidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt N³ -[2-{2-(4-guanidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid TFA salt Methyl N³ -[2-{2-(4-N-hydroxyamidinophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N³ -[2-{2-(4-amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionate N³ -[2-{2-(4-Amidophenyl)-1,3,4-thiadiazol-5-yl}-acetyl]-N² -(3-methylphenylsulfonyl)-2,3-(S)-diaminopropionic acid Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate HCl salt N³ -[2-{2-(4-Amidinophenyl)-1,3,4-thiadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionic acid HCl salt Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N³ -[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}acetyl]-N² -(n-butoxycarbonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt Methyl N³ -[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate Methyl N³ -[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N3-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-yl}-acetyl]-N² -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]glycine TFA salt Methyl N-[2-{2-(4-guanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine TFA salt Ethyl N-[2-{2-(4-amidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-(S)-phenylalanine HCl salt Methyl N2-[2-{2-(4-aminophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N3-(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate TFA salt Methyl N² -[2-{2-(4-N,N'-bis-tert-butoxycarbonylguanidinophenyl)-1,3,4-oxadiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate Methyl N² -[2-{2-(4-amidinophenyl)-1,3,4-thiodiazol-5-ylthio}-acetyl]-N³ -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate HCl salt.
 4. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt from thereof.
 5. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.
 6. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.
 7. A method in inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 1. 8. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 2. 9. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim
 3. 10. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 1. 11. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 2. 12. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim
 3. 